PS-IIDQ: a supported coupling reagent for efficient and general amide bond formation

Article abstract of DOI:10.1016/j.tet.2007.06.019

Polystyrene-IIDQ, a polymer-supported coupling reagent, was synthesized in three steps from Merrifield resin in 86% overall conversion. This reagent efficiently coupled carboxylic acids to amines in good yields and high purities, required no pre-activation step, and was tolerant of the order of reagent addition. PS-IIDQ was observed to be more efficient than polymer-supported carbodiimides (PS-EDC and PS-DCC) and gave higher yields than HATU for general amide bond formation, including the coupling of anilines and hindered substrates. When evaluated with five carboxylic acids and nine amines (including anilines and secondary amines) PS-IIDQ gave an average isolated yield of 73%.

Full text of DOI:10.1016/j.tet.2007.06.019

Tetrahedron 63 (2007) 8855–8871
PS-IIDQ: a supported coupling reagent for efficient and general
amide bond formation
y
*
Eric Valeur and Mark Bradley
Combinatorial Centre of Excellence, School of Chemistry, University of Edinburgh, Edinburgh EH9 3JJ, United Kingdom
Received 20 February 2007; revised 25 May 2007; accepted 7 June 2007
Available online 10 June 2007
Abstract—Polystyrene-IIDQ, a polymer-supported coupling reagent, was synthesized in three steps from Merrifield resin in 86% overall
conversion. This reagent efficiently coupled carboxylic acids to amines in good yields and high purities, required no pre-activation step,
and was tolerant of the order of reagent addition. PS-IIDQ was observed to be more efficient than polymer-supported carbodiimides (PS-
EDC and PS-DCC) and gave higher yields than HATU for general amide bond formation, including the coupling of anilines and hindered
substrates. When evaluated with five carboxylic acids and nine amines (including anilines and secondary amines) PS-IIDQ gave an average
isolated yield of 73%.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
coupling reagents have been immobilized. This is probably
because peptides are usually synthesized directly on a poly-
mer support with the coupling reagent being in solution.
However, amide bonds are found in large numbers of phar-
maceutically relevant compounds, and supported coupling
reagents would therefore be of great interest for general
amide bond formation, especially when it is necessary to
produce libraries of compounds by parallel synthesis.
Over the past decade, interest in the development of new
solid-supported reagents has increased,1 predominantly be-
cause these reagents combine the traditional advantages of
solution-phase chemistry, such as reaction monitoring,
with the solid-phase advantages of being able to drive reac-
tions by mass action, and the associated ease of parallel
synthesis. Ideally, when using solid-supported materials,
unreacted reagents and by-products should remain on the
resin and be easily removed by filtration at the end of the re-
action. However, although the scope of polymer-supported
reagents, such as oxidants, reductants, and catalysts has
broadened considerably in recent years, relatively few
Currently available supported coupling reagents include
a number of immobilized carbodiimides such as PS-EDC2
1 and PS-DCC 2,3 although PS-TBTU4 3 and PS-BOP5 4
have also been immobilized (Fig. 1). However, these two lat-
ter reagents imply the release of uronium or phosphonium
salts into solution during coupling, clearly an undesirable
occurrence for an immobilized reagent as these by-products
have to be removed following synthesis.
Keywords: Coupling reagent; Polymer-supported reagent; Immobilized re-
agent; IIDQ; Parallel synthesis; Amide bond formation; Amidation; Amide.
Abbreviations: BOP, benzotriazolyl-N-oxytrisdimethylaminophosphonium
hexafluorophosphate; BOP-Cl, N,N0-bis(2-oxo-3-oxazolidinyl)-phosphinic
chloride; DCC, dicyclohexyl-carbodiimide; DCE, dichloroethane; DCM,
dichloromethane; DIPEA, N,N-diisopropylethylamine; DMA, dimethylacet-
amide; DMAP, 4-dimethylaminopyridine; DMF, N,N-dimethylformamide;
DMSO, dimethyl-sulfoxide; EDC, 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide; EEDQ, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline;
HOAt, 1-hydroxy-7-azabenzotriazole; HOBt, 1-hydroxy-1H-benzotriazole;
HATU, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluo-
rophosphate; IIDQ, N-isobutoxycarbonyl-2-isobutoxy-1,2-dihydroquino-
line; MP, microporous; MTBD, 7-methyl-1,5,7-triaza-bicyclo[4.4.0]dec-
5-ene; NMM, N-methyl-morpholine; PS, polystyrene; PyAOP, [(7-azaben-
zotriazol-1-yl)oxy]tris-(pyrrolidino)-phosphonium hexafluorophosphate;
SPE, solid-phase extractor; TBTU, O-benzotriazol-1-yl-1,1,3,3-tetramethyl-
uronium tetrafluoroborate; TEA, triethylamine; THF, tetrahydrofuran.
* Corresponding author. Tel.: +44 131 650 4820; fax: +44 131 650 6453;
e-mail: mark.bradley@ed.ac.uk
Solution-phase coupling reagents cover a broad range of
chemistries and include carbodiimides, HOBt/HOAt based
uronium or phosphonium salts such as HATU6 5 and
PyAOP7b 6, reagents that generate acid halides in situ such
as BOP-Cl8 7, and EEDQ 8 (Fig. 2).9 The huge choice of
coupling reagents available provides the chemist with nu-
merous possibilities, however many of the coupling reagents
reported have serious drawbacks or are simply not efficient.
In addition, many of the reagents have been designed for
peptide synthesis, which involves predominantly coupling
with primary amines.
In the synthesis of diverse small molecules, the medicinal
chemist faces the challenges of finding a method to couple
efficiently a broad range of anilines, primary and secondary
y
Present address: Merck-Serono, Medicinal Chemistry Department,
ꢀ
4 Avenue President Mitterand, 91380 Chilly-Mazarin, France.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.019

8856
E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
O
N
N
O
N
N
N+
N
-PF6
N
-PF6
N
N
N
O
.HCl
BF4
NMe2
N
N C
N
N
N
P+
N
Me2N
N
N
+
N
1 PS-EDC
3 PS-TBTU
6
PyAOP
N
5
HATU
O
NMe2
O P NMe2
PF6
O
O
O
S
N
NMe2
O
N
H
N
P
N
Cl
N
N C N
OR
N
O
O
OR
O
2 PS-DCC
4 PS-BOP
8
EEDQ R = Et
7
BOP-Cl
9
IIDQ
R = iBu
Figure 1. Structures of some supported coupling reagents.
Figure 2. Structures of coupling reagents.
amines, and bulky substrates whose reactivities should (in
order to achieve a diverse range of products) be widely vari-
able. However, none of the reagents reported to date can
achieve this routinely with good conversion, and most cou-
pling reagents have one or more of the following drawbacks.
(1) The structure of the reagent means that side-reactions
will occur in the presence of nucleophiles. This is particu-
larly the case with uronium-type reagents, which can yield
guanidinium species in the presence of amines. (2) A pre-ac-
tivation step is often necessary: the carboxylic acid has to be
added to the coupling reagent prior to the addition of the
amine. This has an impact particularly in parallel synthesis
where the pre-activated species may decompose. (3) Many
reagents require the use of a base in order to activate the cou-
pling agent, however many reagents exhibit poor stability in
the presence of the base. For example, only 36% of the cou-
pling reagent HATU 5 remains after 1 h in the presence of
1 equiv of DIPEA in DMF.7a
toward amines (no pre-activation needed) while also gener-
ating a base during the reaction, which makes the use of an
additional base redundant. Their lack of use can perhaps be
explained by the fact that the by-product of the reaction,
quinoline, is often hard to separate from the product.
2.1. Comparison of EEDQ and IIDQ
Their potential was initially assessed by investigating the
relative solution coupling reactivities of EEDQ 8 and IIDQ
9 with three amines (4-tert-butylaniline, benzylamine, and
morpholine) and two carboxylic acids (benzoic acid and
phenylacetic acid). The results are presented in Table 1.
Yields were good with benzylamine and anilines, but only
moderate when using morpholine. Overall these results
showed that IIDQ was slightly more efficient than EEDQ,
and IIDQ was therefore selected for comparison tests against
other common coupling reagents.
The ideal coupling reagent should therefore have the follow-
ing characteristics. (1) No pre-activation step should be nec-
essary, with the added flexibility of being able to add the
reactants in any order and at any time. (2) No particular spec-
ificity for amino-acids, the reagent should be useful for gen-
eral amide bond formation. (3) There should be no need of
any other additive such as a base to achieve efficient cou-
pling. (4) No racemization when coupling chiral amines or
acids. (5) No non-volatile by-products left behind in solution.
2.2. Comparison of IIDQ, HATU, BOP-Cl, and PyAOP
In order to compare the coupling efficiency of IIDQ with
three other widely used coupling reagents (HATU 5, PyAOP
6, and BOP-Cl 7) (without pre-activation) four amines and
three carboxylic acids were tested. The synthesis was carried
out in CH3CN (because of its ability to dissolve carboxylic
acids and its ease of evaporation which is important for
use in parallel synthesis) with 1 equiv of each reactant/re-
agent. After the reaction, the mixtures were passed through
an SPE cartridge containing a mixed bed of sulfonic acid/
quaternary ammonium hydroxide ion-exchange resins, in
order to scavenge any unreacted materials. The results are
2. Results and discussion
EEDQ 8 and IIDQ 935 are interesting, yet under-used, cou-
pling reagents, which have the advantages of being inert
Table 1. Coupling comparison of EEDQ and IIDQ
Entry
Amide
Amine
Acid
IIDQ
EEDQ
Yielda
Purityb
Yielda
Purityb
1
2
3
4
5
6
10
11
12
13
14
15
4-tert-Butyl-aniline
Benzylamine
Morpholine
4-tert-Butyl-aniline
Benzylamine
Morpholine
Phenylacetic acid
Phenylacetic acid
Phenylacetic acid
Benzoic acid
Benzoic acid
Benzoic acid
96
91
38
88
85
50
100
100
100
100
100
99
94
87
32
85
66
41
100
100
93
100
100
95
Average
76
100
67
98
a
Isolated yield.
Purity determined by ELSD.
b

E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
Table 3. Comparison of the yields obtained using IIDQ and HATU
8857
shown in Table 2 and clearly demonstrated that IIDQ 9 gen-
erally gave highly pure products. It was interesting to note
that quinoline was removed via filtration through the SPE.
For the other coupling reagents, their many products of de-
composition remained in the reaction mixture yielding
much less pure products. However, HATU 5 performed sur-
prisingly well considering its poor stability, but this could be
explained by the absence of a tertiary base during coupling.
In fact, in terms of purities HATU 5 performed as well as
IIDQ 9. Due to the high purities obtained when using
IIDQ 9 or HATU 5, the isolated yields obtained when using
these two coupling reagents were compared (Table 3). Most
of the substrates chosen were coupled in good yields but
morpholine gave relatively poor conversion, emphasizing
the usual difficulty of coupling secondary amines. Overall,
IIDQ performed better than HATU 5 in terms of yield. These
studies showed that IIDQ 9 could potentially be used as
a coupling reagent for efficient, general amide bond forma-
tion without requiring a pre-activation step. Attachment of
IIDQ 9 onto a resin would allow immobilization of the quin-
oline by-product, obtained during the reaction process elim-
inating the need for SPE purification.10 A simple filtration
would therefore yield the pure product and isobutanol (boil-
ing point: 108 ꢀC) that could be removed in vacuo.
Entry Amide Amine
Acid
IIDQ HATU
1
2
3
16
17
18
4-tert-Butyl-aniline
Benzylamine
1,2,3,4-Tetrahydro-
naphthalen-1-ylamine
Morpholine
4-tert-Butyl-aniline
Benzylamine
1,2,3,4-Tetrahydro-
naphthalen-1-ylamine
Morpholine
4-tert-Butyl-aniline
Benzylamine
1,2,3,4-Tetrahydro-
naphthalen-1-ylamine
Morpholine
Z-Ala-OH
Z-Ala-OH
Z-Ala-OH
93
86
71
38
53
37
4
5
6
7
19
10
11
20
Z-Ala-OH
69
54
31
55
37
Phenylacetic acid 80
Phenylacetic acid 58
Phenylacetic acid 59
8
9
10
11
12
13
14
21
Phenylacetic acid 33
53
33
52
37
Benzoic acid
Benzoic acid
Benzoic acid
89
88
67
12
15
Benzoic acid
Yield average
48
70
50
44
intermediate 26, which could be quenched with isobutanol
to form polymer-supported IIDQ 27 (Scheme 1). The trans-
formation appeared to be successful by IR (Fig. 4, conversion
was evaluated via integration of the carbamate band using
one of the resin backbone bands at 1490 cmꢁ1 as a reference)
1
and was confirmed by MAS-NMR. Figure 5 shows the H
NMR spectrum of IIDQ 9 in solution and the H MAS-
NMR spectrum of polymer-supported IIDQ 27, while
1
2.3. Synthesis of PS-IIDQ
1
a H–1H COSY spectra confirmed the correlation between
H-12 and H-13 and H-16 and H-17.
The coupling of commercially available 6-hydroxyquinoline
23 onto Merrifield resin 22 (Polymer Laboratories,
3.99 mmol/g, microporous, 150–300 mm) was performed
in DMA at reflux in the presence of a large excess of potas-
sium carbonate as shown in Scheme 1. After 6 h, the IR spec-
trum revealed almost complete conversion, while leaving the
reaction mixture for a longer reaction time was disadvanta-
geous as insoluble by-products started to form (leading to
clogging of the resin). Nitrogen and chlorine analysis of
the resin after 6 h revealed a 98% conversion with a loading
of 2.74 mmol/g (the ‘apparent’ reduction in loading is due to
the mass increase in the resin as the chloride is displaced by
the 6-hydroxyquinoline). The structure of PS-quinoline 24
was confirmed by Magic-Angle Spinning NMR and the
spectrum obtained compared favorably to the solution NMR
of 6-benzyloxy-quinoline 25 (Fig. 3).
Other bases (TEA, NMM, pyridine, 2,6-lutidine, N-methyl-
piperidine, 2,6-di-tert-butyl-4-methyl-pyridine, DMAP,
MTBD, 2-tert-butyl-1,1,3,3-tetramethylguanidine) and sol-
vents (DCM, THF, dioxane, CH3CN, DMSO, DMF) were
investigated in this step but DIPEA and DCM outperformed
then all.
As only carbon, hydrogen, and oxygen atoms were added
during the conversion of PS-quinoline into PS-IIDQ elemen-
tal analysis was not a suitable method for determination of
the final loading of the reagent (the resin dominates the
C/H balance). Therefore, a known mass of IIDQ resin was
used to couple an excess of phenylacetic acid and benzyl-
amine and the product isolated and quantified. The yield of
the reaction thus gave the practical and accessible loading
of the resin. Using this method, a loading of 1.68 mmol/g
was determined corresponding to a conversion of 88%
The reaction of isobutyl chloroformate with the supported
€
quinoline in the presence of Hunig’s base yielded a reactive
Table 2. Comparison of the compound purities obtained (determined by ELSD) using the coupling reagents IIDQ, PyAOP, BOP-Cl, and HATU
Entry
Amide
Amine
Acid
IIDQ
PyAOP
BOP-Cl
HATU
1
2
3
4
5
6
7
8
16
17
18
19
10
11
20
12
13
14
21
15
4-tert-Butyl-aniline
Benzylamine
1,2,3,4-Tetrahydro-naphthalen-1-ylamine
Morpholine
4-tert-Butyl-aniline
Benzylamine
1,2,3,4-Tetrahydro-naphthalen-1-ylamine
Morpholine
4-tert-Butyl-aniline
Benzylamine
1,2,3,4-Tetrahydro-naphthalen-1-ylamine
Morpholine
Z-Ala-OH
Z-Ala-OH
Z-Ala-OH
Z-Ala-OH
Phenylacetic acid
Phenylacetic acid
Phenylacetic acid
Phenylacetic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
100
100
100
100
100
100
100
87
100
100
100
39
85
97
99
95
84
95
96
8
84
90
91
7
3
89
94
92
0
12
80
2
100
100
100
100
100
100
100
100
100
100
100
42
9
0
10
11
12
27
83
0
Purity average
94
78
53
95

8858
E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
HO
K2CO3, KI
O
Cl
DMA, reflux, 6 h
N
N
22
23
24
3.99 mmol/g
2.74 mmol/g
i
1) BuOCOCl, DiPEA
DCM, 0 °C, 3 h
O
O
16
i
N
O
2) BuOH, rt, 16 h
17
N
Cl
O
O
O
O
12
27
13
26
1.68 mmol/g
Scheme 1. Synthesis of polymer-supported IIDQ (PS-IIDQ).
Figure 3. Comparison of the 1H NMR spectra of 6-benzyloxyquinoline and 1H PS-quinoline (MAS).
from the supported quinoline 24 into the supported IIDQ 27
(assuming complete reaction of the immobilized reagent
with phenylacetic acid and benzylamine).
In order to determine the optimal coupling conditions for
PS-IIDQ, the coupling between benzylamine and phenylace-
tic acid was performed in different solvents. DCM was the
first solvent tested and this proved to work efficiently as
shown in Table 4 (entry 1). However, the choice of DCM
was not optimal, because many carboxylic acids are insolu-
ble in it, while it is too volatile for parallel synthesis use. In
order to solve these problems, DMF, DMA, CH3CN, THF,
dioxane, and DCE were also evaluated. The results shown
in Table 4 showed that DMF (entry 2) or DMA (entry 3) per-
formed worse than DCM (entry 1). DCE (entry 7) gave sim-
ilar results to DCM, but its choice was again not optimal in
Figure 4. IR spectrum of PS-IIDQ.

E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
8859
Figure 5. Comparison of the 1H NMR spectra of IIDQ and PS-IIDQ (MAS).
Table 4. Solvent optimization for the coupling of benzylamine (1 equiv) and
phenylacetic acid (1 equiv) with PS-IIDQ (3 equiv)
hour, a characteristic, which is unsuitable for hindered sub-
strates or if the coupling is slow. In this respect, PS-IIDQ 27
offered a good balance between reactivity and stability.
Entry
Solvent
Yield
1
2
3
4
5
6
7
DCM
DMF
DMA
CH3CN
THF
98
32
37
91
64
87
94
HATU 5 (5 min pre-activation) gave lower yields than PS-
IIDQ 27. In particular couplings with HATU 5 using amino-
isobutyric acid (entries 1–3) and/or anilines (entries 1, 4, and
7) were significantly poorer. Results were quite poor for the
supported carbodiimides. PS-EDC gave an average yield of
41% while PS-DCC gave only 26%, in comparison to the
average 71% yield obtained with PS-IIDQ. Both supported
carbodiimides were less efficient than PS-IIDQ, making
PS-IIDQ a reagent of choice for parallel solution-phase
libraries.
Dioxane
DCE
terms of acid solubility. THF (entry 5) was not efficient,
while dioxane (entry 6) also gave acceptable results. The
best compromise was acetonitrile, which gave comparable
conversion to DCM but with better acid solubility and re-
duced volatility. Therefore, acetonitrile was chosen as the
coupling solvent, although it is known generally as having
poor swelling properties for polystyrene supports.11 The
quantity of coupling reagent required for efficient coupling
was also investigated: 1.5 equiv of PS-IIDQ only gave
67% yield, while 2 or 3 equiv typically gave 80–85% yields.
2.5. Scope and limitations of PS-IIDQ
Polymer-supported IIDQ was efficient even when using hin-
dered substrates and to explore this in more detail a compre-
hensive study of the scope and limitations of the reagent was
carried out (Table 6). All building blocks were commercially
available, except H-Aib-OMe 33, which was prepared fol-
lowing a literature procedure.12 Coupling was realized using
the optimized conditions, and any unreacted amine and carb-
oxylic acid were removed either by ion-exchange resins
(Amberlyst 15 and 26) or by an aqueous workup (entries
3, 9, 15, 21, 26, 29, and 34), depending on the presence of
acidic or basic labile protecting groups on the amine and/
or carboxylic acid. PS-IIDQ succeeded, in almost all cases,
in coupling the amine to the acid in excellent purities. Yields
were good even when coupling hindered substrates such as
aminoisobutyric acid methyl ester to any of the different
acids (entries 3, 9, 15, 21, and 29). Similarly, phenylglycine
methyl ester was coupled to Z-Ala-OH or phenoxyacetic
acid in high yield (entries 26 and 34). In addition secondary
2.4. Comparison of PS-IIDQ with commercial coupling
reagents
PS-IIDQ 27 was compared to some commercially available
coupling reagents: HATU 5 and two polymer-supported
carbodiimides PS-EDC 1 and PS-DCC 2 (Table 5). The
coupling was realized using CH3CN as solvent, 2 equiv of
coupling reagent and 1 equiv of amine and acid, and a cou-
pling time of 24 h in order to enable difficult substrates to re-
act. This time-frame contrasts with many coupling reagents,
which usually have very high reactivity but are unstable in
solution with most of the reagent being degraded after an

8860
E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
Table 5. Comparison of PS-IIDQ with some commonly utilized coupling reagents
Entry
Amide
PS-IIDQ
HATUc
Purityb
PS-EDC
PS-DCC
Yielda
Purityb
Yielda
42
Yielda
Purityb
Yielda
Purityb
tBu
O
H
1
2
3
4
5
6
28
29
30
10
11
31
69
66
64
60
80
61
100
100
93
15
39
24
68
48
49
100
16
17
24
41
25
35
100
N
N
H
Boc
O
H
N
100
100
100
100
100
45
48
43
69
77
87
95
94
86
N
H
Boc
O
Ph
H
N
O
100
100
100
92
N
H
Boc
O
tBu
O
100
100
100
100
100
100
N
H
O
N
H
O
Ph
O
N
H
O
tBu
O
7
13
89
85
100
100
45
68
100
100
44
48
100
81
28
24
100
95
N
H
O
8
9
14
32
N
H
O
Ph
O
75
72
100
100
54
55
100
98
33
41
100
96
24
26
100
97
N
H
O
Average
a
Isolated yield.
Purity determined by ELSD.
A 5 min activation time was applied when using HATU.
b
c
amines were successfully coupled, including morpholine
(entries 1, 7, 13, 19, and 27) and proline (entries 6, 12, and
18). PS-IIDQ did fail to couple 4-nitroaniline to any of the
acids, which is perhaps not surprising as nitroanilines are
some of the hardest amines to couple in view of the electron
withdrawing nitro group. The yield was also very low when
coupling aminoisobutyric acid to proline benzyl ester 61 (en-
try 6). Similarly, the amides obtained when coupling proline
benzyl ester to phenylacetic acid and benzoic acid needed
purification due to the formation of a carbamate by-product.
However, the global library was successful as two thirds of
the substrates gave the expected amides in yields over
67%, with an average yield of 73% for the reactions yielding
the expected products (Fig. 6).
a carbamate 63 (Scheme 2). Compound 61 was coupled to
15 carboxylic acids with various groups in the a and b posi-
tions (Table 7) and the expected amide and the carbamate by-
products 63 were separated by column chromatography after
aqueous workup of the reaction mixtures. When the a-carbon
The formation of a carbamate by-product can occur during
the PS-IIDQ mediated coupling once the carbonic anhydride
60 has been generated. The amine (proline benzyl ester 61)
can react at either of the two electrophilic centers, the carbon
of the carboxylic acid, yielding the expected amide 62, or
at the carbon of the carbonic anhydride itself, yielding
Figure 6. Library synthesis and overview of yields when using PS-IIDQ as
the coupling reagent.

E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
8861
Table 6. Scope and limitation of PS-IIDQ
Table 6. (continued)
Entry
Amide
Amine
Carboxylic acid
Yield
44
Entry
22
Amide
Amine
Carboxylic acid
Yield
O
H
N
50
0
NH2
O2N
1
34
NH
O
OH
Z
23
18
64
2
3
4
35
36
37
61
67
0
NH2
NH2
NH2
O
24
25
16
17
70
76
t-Bu
NH2
NH2
O
NH2
O2N
O
NH2
26
27
28
29
30
51
52
53
54
55
83
80
52
70
0
O
5
6
38
39
74
3
NH2
Ph
NH
O
O
O
O
OH
Bn
O
HN
NH2
NH2
OH
7
12
40
41
42
77
44
73
0
NH
O
O
O
O
8
NH2
NH2
O
NH2
O2N
9
O
31
32
33
34
56
57
58
59
74
83
82
82
10
O2N
NH2
NH2
11
12
20
43
74
60
t-Bu
NH2
NH2
O
NH2
NH2
Bn
O
HN
O
O
13
14
15
44
77
84
NH
O
O
OH
Ph
NH2
of the acid was not sterically too hindered, that is to say, when
it was linked to just one group and two hydrogens, the major
product obtained was the expected amide (entry 14). On the
other hand when the a-carbon was more hindered (such as
two methyl groups) the carbamate 63 was almost the exclu-
siveproduct (entry 13). Benzoic acid(entry 15) gaveinterme-
diate results. The presence of bulky groups at the a position
clearly increased the quantity of by-product (entry 5). One of
the dominant effects seemed to be the presence of a methyl
group in the a position, which increased dramatically by-
product generation (compare entries 9 and 14), although
two phenyl groups in the a position had little effect (entry 4).
O
15
16
45
46
91
0
NH2
O
NH2
O2N
17
21
83
NH2
O
18
19
47
19
34
79
71
Bn
O
HN
O
When going from a cyclohexyl to a cyclopentyl carboxylic
acid group the percentages inverted (entries 10 and 11).
This study showed a limitation of PS-IIDQ but no real rule
could be established for the influence of groups on the carb-
oxylic acid. However, this side-reaction was observed
only with proline, other secondary amines were unaffected
and we hypothesize that interactions with the proline ester
with the mixed anhydride may be responsible for this alter-
native pathway.
NH
O
Z
NH OH
20
21
48
49
NH2
NH2
O
82
O
(continued)

8862
E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
Table 7. (continued)
O
O
O
60
PS-IIDQ
R
OH
Entry Amide
Carboxylic acid
Amide Carbamate Relative
yield
R
O
O
yield
percentage
O
HN
10
11
73
74
30
55
35/65
61
OH
O
BnO
O
55
49
26
47
68/32
51/49
OH
N
N
O
R
O
OBn
O
OBn
O
O
O
OH
12
75
62
63
N
Boc
Scheme 2. Side-reaction observed when coupling a carboxylic acid to
proline benzyl ester using PS-IIDQ.
O
H
N
13
14
39
43
3
38
4
8/92
94/6
OH
OH
Z
The above examples show that PS-IIDQ worked very effi-
ciently for general amide bond formation. In order to apply
PS-IIDQ for coupling amino-acids, the extent of epimeriza-
tion during segment coupling had to be evaluated. The
60
O
O
Table 7. Evaluation of the influence of various carboxylic acids on the side-
reaction observed with H-Pro-OBn 61
15
47
34
53
39/61
OH
Entry Amide
Carboxylic acid
Amide Carbamate Relative
percentage
yield
yield
classic method to achieve this is to carry out the Anteunis
test, via the coupling between Z-Gly–L-Phe-OH and H-L-
Val-OMe.13 This test is particularly robust as amide cycliza-
tion to give the oxazolone is a real issue for dipeptides.
Coupling between Z-Gly–L-Phe-OH and H-L-Val-OMe
with PS-IIDQ gave the expected tripeptide 76 in 65% yield
without any epimerization detected by 1H NMR (400 MHz)
(the other isomer 77 was synthesized separately). This un-
ambiguously confirmed the absence of epimerization with
PS-IIDQ (Fig. 7).
O
1
2
64
65
43
24
64/36
OH
O
76
18
13
74
85/15
20/80
OH
O
3
4
66
67
OH
O
OH
50
20
71/29
Cl
O
5
6
7
68
69
70
35
66
48
51
22
37
41/59
75/25
56/44
OH
O
OH
Figure 7. NMR evidence showing the absence of epimerization when using
PS-IIDQ. The NMR resonances shown correspond to the CH-a group of the
phenylalanine residue in the peptide Z-Gly-L-Phe-L-Val-OMe.
O
OH
O
The possibility of recycling/regenerating PS-IIDQ was in-
vestigated. Thus the resin used for couplings was washed
extensively with various solvents (THF/H2O 1/1, MeOH,
DCM, Et2O). Then the procedure used previously to trans-
form PS-quinoline into PS-IIDQ was applied, and the load-
ing evaluated by coupling phenylacetic acid to benzylamine.
The same regeneration process was carried out three times
with little variation in loading levels (Table 8).
8
9
71
72
57
35
17
24
77/23
OH
O
59/41
OH
(continued)

E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
8863
Table 8. Recycling of PS-IIDQ (loading was determined by saturation cou-
pling of benzylamine with phenylacetic acid with a known mass of resin and
thus sets the lower limit on available or practical resin loading)
B (column 2, H2O/MeOH, 10 min): 0 min (95/5), 7 min
(5/95), 9 min (5/95). Method C (column 3, H2O/MeOH,
15 min): 0 min (95/5), 12 min (5/95), 14 min (5/95). Melting
points (Pyrex capillaries) are uncorrected. HRMS analyses
were performed by the Mass Spectrometry Service of the
University of Southampton, UK. Elemental analyses were
carried out by Medac Ltd, UK.
Cycle
Loading (mmol/g)
1
2
3
4
ꢃ1.68
ꢃ1.71
ꢃ1.65
ꢃ1.64
4.1.1. Synthesis of a library for comparison of IIDQ and
EEDQ. The following mother solutions were prepared: tert-
butyl aniline: 207 mL (0.5 mmol) in 5 mL CH3CN
(0.1 mmol/mL), benzylamine: 143 mL (0.5 mmol) in 5 mL
CH3CN (0.1 mmol/mL), morpholine: 114 mL (0.5 mmol)
in 5 mL CH3CN (0.1 mmol/mL), phenylacetic acid: 95 mg
(0.7 mmol) in 7 mL CH3CN (0.1 mmol/mL), benzoic acid:
85 mg (0.7 mmol) in 7 mL CH3CN (0.1 mmol/mL), IIDQ:
212 mg (0.7 mmol) in 7 mL CH3CN (0.1 mmol/mL),
EEDQ: 172 mg (0.7 mmol) in 7 mL CH3CN (0.1 mmol/
mL). Procedure. In each vial, a solution of an amine
(1 mL, 0.1 mmol, 1 equiv) and carboxylic acid (1 mL,
0.1 mmol, 1 equiv) were added, followed by the addition
of a solution of a coupling reagent (1 mL, 0.1 mmol,
1 equiv). The 12 vials were shaken at room temperature
for 16 h. The contents of the vials were filtered through an
SPE cartridge containing a mixed bed of MP acidic/basic
ion-exchange resins (Polymer Lab, 500 mg). The filtrates
were concentrated in vacuo to afford the compounds listed
below.
3. Conclusion
PS-IIDQ is a high loading, efficient polymer-supported
coupling reagent for general amide bond formation, includ-
ing hindered substrates and anilines. It is also suitable for
coupling of amino-acids as the epimerization levels were
low. PS-IIDQ proved to be more efficient than other com-
mercially available polymer-supported coupling reagents
(PS-EDC, PS-DCC) and also better than the powerful and
widely used HATU. One limitation of this new reagent
was observed, but this was noticed only with proline. Stabil-
ity, ease of recycling, convenient procedures for parallel
amide bond formation, good yields, and high purities
make PS-IIDQ a reagent of choice for N-acylation in organic
chemistry, especially for parallel synthesis.14
4. Experimental
4.1. General
4.1.1.1. N-(4-tert-Butyl-phenyl)-2-phenyl-acetamide
(10). The title compound was obtained as an off-white solid
(25 mg, 96%). HPLC (method B): tR¼7.32 min. Purity
1
The reagents commercially available were used without fur-
ther purification. Solvents were not dried or distilled except
where specified. NMR spectra were recorded on Bruker
DPX 400 and 300, or ARX 250 spectrometers in the solvents
indicated at 298 K. Chemical shifts are reported on the
d scale in parts per million and are referenced to residual
non-deuterated solvent resonances. All 13C NMR experi-
ments were supported with DEPT. IR spectra were obtained
on a Thermo Mattson Satellite FTIR spectrometer or a
Bruker Tensor 27 Spectrometer, with 16 scans, at a resolution
of ꢂ4 cmꢁ1. The FTIR spectrometers were fitted with a
Specac single reflection diamond ATR Golden Gate, and
neat compounds or resins were used for analysis. Frequen-
cies are reported in cmꢁ1 and only frequencies correspond-
ing to significant functional groups are reported. LC–mass
spectra were recorded either on a Waters ZMD single quad-
rupole MS, with a 2700 Autosampler and a 600 Pump, or an
Agilent Technologies LC/MSD 1100 Quadrupole Mass
Spectrometer (QMS), both with an electrospray ion source.
HPLC spectra were obtained on an Agilent 1100 coupled
to a Polymer Lab 100 ES Evaporative Light Scattering
Detector (ELSD), with a Phenomenex Luna C18, 5 mm,
10 cm column (column 1), a Phenomenex Gemini C18,
5 mm, 10 cm column (column 2), or a Phenomenex Luna
C18, 5 mm, 15 cm column (column 3). HPLC grade water,
MeOH or CH3CN with 0.1% formic acid were used as elu-
ants, at a flow rate of 1 mL/min, with samples prepared to
a concentration of about 30 mg mLꢁ1 (ZMD) or 1 mg mLꢁ1
(Agilent) and filtered prior to injection. The following
methods were used. Method A (column 1, H2O/MeOH,
12 min): 0 min (95/5), 7 min (5/95), 9 min (5/95). Method
(ELSD): 100%. H NMR (250 MHz, CDCl3): 7.48 (s, 1H,
NH), 7.39–7.25 (m, 9H, Ar–H), 3.69 (s, 2H, CH2), 1.28 (s,
9H, C(CH3)3). 13C NMR (75 MHz, CDCl3): 169.16
(C]O), 147.32 (C–Ar), 135.02 (C–Ar), 134.61 (CH–Ar),
129.38 (CH–Ar), 129.02 (CH–Ar), 127.42 (CH–Ar),
125.63 (CH–Ar), 119.71 (CH–Ar), 44.60 (CH2), 34.27
(C(CH3)3), 31.27 (C(CH3)3). FTIR (neat): 3285 (m), 1655
(s). Mp: 146–148 ꢀC (methanol). HRMS (ES): calcd for
C18H21NO: 268.1696 (M+H)+. Found: 268.1696.
4.1.1.2. N-Benzyl-2-phenyl-acetamide15 (11). The title
compound was obtained as a white solid (20 mg, 91%).
1
HPLC (method A): tR¼7.66 min. Purity (ELSD): 96%. H
NMR (300 MHz, CDCl3): 7.29–7.08 (m, 10H, Ar–H), 5.71
(br s, 1H, NH), 4.32 (d, J¼5.7 Hz, 2H, NHCH2), 3.53
(s, 2H, CH2). m/z (ESMS): 226 (M+H)+ (85%), 248
(M+Na)+ (100%). Mp: 119–121 ꢀC (ethanol, lit.:15 118–
120 ꢀC).
4.1.1.3. 4-Phenylacetyl-morpholine16 (12). The title
compound was obtained as a colorless oil (8 mg, 38%).
HPLC (method C): tR¼8.11 min. Purity (ELSD): 100%.
1H NMR (250 MHz, CDCl3): 7.36–7.23 (m, 5H, Ar–H),
3.74 (s, 2H, Ar–CH2), 3.65–3.46 (m, 8H, CH2). m/z
(ESMS): 206 (M+H)+ (46%), 228 (M+Na)+ (100%). Mp:
60–63 ꢀC (ethanol, lit.:16 60–62 ꢀC).
4.1.1.4. N-(4-tert-Butyl-phenyl)-benzamide17 (13). The
title compound was obtained as a white solid (22 mg, 88%).
HPLC (method B): tR¼7.29 min. Purity (ELSD): 100%. 1H
NMR (250 MHz, CDCl3): 7.96 (br s, 1H, NH), 7.87–7.84

8864
E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
(m, 2H, OC–C–CH), 7.59–7.35 (m, 7H, Ar–H), 1.32 (s, 9H,
C(CH3)3). m/z (ESMS): 254 (M+H)+ (65%), 276 (M+Na)+
(61%), 529 (2M+Na)+ (100%). Mp: 142–143 ꢀC (ethanol,
lit.:18 143–144 ꢀC).
4.1.2.2. ((S)-1-Benzylcarbamoyl-ethyl)-carbamic acid
benzyl ester (17). The title compound was obtained as a
white solid (27 mg, 86%). HPLC (method C): tR¼9.77 min.
1
Purity (ELSD): 100%. H NMR (300 MHz, CDCl3): 7.38–
7.21 (m, 10H, Ar–H), 6.61 (br s, 1H, NH), 5.46 (br d,
J¼7.2 Hz, 1H, NH), 5.03 (AB-d, J¼12.5 Hz, 2H, OCH2),
4.40 (dd, J¼2.2 Hz and 5 Hz, 2H, NHCH2), 4.35–4.22 (m,
1H, CH), 1.39 (d, J¼7.0 Hz, 3H, CH3). 13C NMR
(75 MHz, CDCl3): 172.34 (C]O), 155.97 (C]O), 137.88
(C–Ar), 136.05 (C–Ar), 128.57 (CH–Ar), 128.43 (CH–Ar),
128.10 (CH–Ar), 127.88 (CH–Ar), 127.49 (CH–Ar),
127.37 (CH–Ar), 66.87 (OCH2), 50.52 (CH), 43.36
(NHCH2), 18.71 (CH3). FTIR (neat): 3297 (w), 3279 (m),
1684 (s), 1640 (s). Mp: 129–131 ꢀC (methanol). HRMS
(ES): calcd for C18H20N2O3: 313.1547 (M+H)+. Found:
313.1547.
4.1.1.5. N-Benzyl-benzamide19 (14). The title com-
pound was obtained as a white solid (18 mg, 85%). HPLC
1
(method A): tR¼7.52 min. Purity (ELSD): 100%. H NMR
(300 MHz, CDCl3): 7.74–7.71 (m, 2H, OC–C–CH), 7.46–
7.19 (m, 8H, Ar–H), 6.51 (br s, 1H, NH), 4.56 (d, J¼
5.7 Hz, 2H, CH2). m/z (ESMS): 212 (M+H)+ (72%), 234
(M+Na)+ (100%). Mp: 106–107 ꢀC (ethanol, lit.:20 105–
106 ꢀC).
4.1.1.6. 4-Benzoyl-morpholine21 (15). The title com-
pound was obtained as a white solid (9 mg, 50%). HPLC
1
(method C): tR¼7.59 min. Purity (ELSD): 100%. H NMR
(300 MHz, CDCl3): 7.42–7.37 (m, 5H, Ar–H), 3.85–3.44
(m, 8H, CH2). m/z (ESMS): 192 (M+H)+ (100%). Mp: 73–
74 ꢀC (ethanol, lit.:21 72 ꢀC).
4.1.2.3. [(S)-1-(1,2,3,4-Tetrahydro-naphthalen-1-yl-
carbamoyl)-ethyl]-carbamic acid benzyl ester (18). The
title compound was obtained as a white solid (25 mg, 71%).
HPLC (method C): tR¼10.55 min. Purity (ELSD): 100%. 1H
NMR (300 MHz, CDCl3): 7.37–7.05 (m, 9H, Ar–H),
6.44 (br s, 1H, NH), 5.48 (br s, 1H, NH), 5.12 (m, 1H,
NHCH naphthyl), 4.99 (s, 2H, OCH2), 4.26 (m, 1H, CH*),
2.78–2.69 (m, 2H, Ar–CH2 naphthyl), 2.02–1.97 (m, 1H,
CH naphthyl), 1.82–1.78 (m, 3H, CH naphthyl), 1.42 (dd,
J¼6.9 Hz and 3.3 Hz, 3H, CH3). 13C NMR (75 MHz,
CDCl3): 171.49 (C]O), 155.84 (C]O), 137.50 (C–Ar),
136.32 (C–Ar), 136.18 (C–Ar), 129.14 (CH–Ar), 128.47
(CH–Ar), 128.41 (CH–Ar), 128.14 (CH–Ar), 127.96 (CH–
Ar), 127.30 (CH–Ar), 127.26 (CH–Ar), 126.26 (CH–Ar),
66.91 (OCH2), 50.68 (CH naphthyl), 47.54 (CH*), 30.10
(CH2), 29.16 (CH2), 19.99 (CH2), 18.94 (CH3). FTIR
(neat): 3289 (m), 1687 (s), 1639 (s). Mp: 130–132 ꢀC (meth-
anol). HRMS (ES): calcd for C21H24N2O3: 353.1865
(M+H)+. Found: 353.1862.
4.1.2. Synthesis of the library and comparison of IIDQ,
PyAOP, BOP-Cl and HATU. The following mother solu-
tions were prepared: tert-butyl aniline: 207 mL (1.3 mmol)
in 13 mL CH3CN (0.1 mmol/mL), benzylamine: 143 mL
(1.3 mmol) in 13 mL CH3CN (0.1 mmol/mL), 1,2,3,4-tetra-
hydro-naphthalen-1-ylamine: 137 mL (1.3 mmol) in 13 mL
CH3CN (0.1 mmol/mL), morpholine: 114 mL (1.3 mmol)
in 13 mL CH3CN (0.1 mmol/mL), Z-Ala-OH: 469 mg
(2.1 mmol) in 21 mL CH3CN (0.1 mmol/mL), phenylacetic
acid: 285 mg (2.1 mmol) in 21 mL CH3CN (0.1 mmol/
mL), benzoic acid: 257 mg (2.1 mmol) in 21 mL CH3CN
(0.1 mmol/mL), IIDQ: 485 mg (1.6 mmol) in 16 mL
CH3CN (0.1 mmol/mL), PyAOP: 836 mg (1.6 mmol) in
16 mL CH3CN (0.1 mmol/mL), BOP-Cl: 407 mg
(1.6 mmol) in 16 mL CH3CN (0.1 mmol/mL), HATU:
608 mg (1.6 mmol) in 16 mL CH3CN (0.1 mmol/mL). Pro-
cedure. In each vial, a solution of an amine (1 mL,
0.1 mmol, 1 equiv) and of a carboxylic acid (1 mL,
0.1 mmol, 1 equiv) were added, followed by the addition of
a coupling reagent (1 mL, 0.1 mmol, 1 equiv). The 48 vials
were shaken at room temperature for 16 h. The contents of
the vials were then filtered through an SPE cartridge contain-
ing a mixed bed of MP acidic/basic ion-exchange resins
(Polymer Lab, 500 mg). The filtrates were concentrated in
vacuo to afford the compounds listed below.
4.1.2.4. ((S)-1-Methyl-2-morpholin-4-yl-2-oxo-ethyl)-
carbamic acid benzyl ester (19). The title compound was
obtained as a white solid (20 mg, 69%). HPLC (method
C): tR¼8.72 min. Purity (ELSD): 100%. 1H NMR
(300 MHz, CDCl3): 7.34–7.29 (m, 5H, Ar–H), 5.83 (d, J¼
6.9 Hz, 1H, NH), 5.09 (s, 2H, Ar–CH2), 4.64 (quint., J¼
6.0 Hz, 1H, CH), 3.73–3.43 (m, 8H, CH2 morpholine),
1.32 (d, J¼6.9 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3):
170.89 (C]O), 155.51 (C]O), 136.35 (C–Ar), 128.46
(CH–Ar), 128.06 (CH–Ar), 127.99 (CH–Ar), 66.73 (OCH2
morpholine), 66.47 (OCH2Ph), 46.49 (CH), 45.882 (N–
CH2), 19.23 (CH3). FTIR (neat): 3307 (w), 3289 (w), 1711
(s), 1638 (s). Mp: 134–136 ꢀC (ethanol). HRMS (ES): calcd
for C15H20N2O4: 293.1496 (M+H)+. Found: 293.1494.
4.1.2.1. [(S)-1-(4-tert-Butyl-phenylcarbamoyl)-ethyl]-
carbamic acid benzyl ester (16). The title compound was
obtained as a pale orange solid (33 mg, 93%). HPLC
(method C): tR¼10.96 min. Purity (ELSD): 100%. 1H
NMR (250 MHz, CDCl3): 8.38 (br s, 1H, Ar–NH), 7.49–
7.28 (m, 9H, Ar–H), 5.62 (br d, J¼7.5 Hz, 1H, CH–NH),
5.12 (AB-d, J¼12.25 Hz, 2H, OCH2), 4.49–4.38 (m, 1H,
CH), 1.45 (d, J¼7.2 Hz, 3H, CH3), 1.29 (s, 9H, C(CH3)3).
13C NMR (75 MHz, CDCl3): 170.44 (C]O), 156.33
(C]O), 147.40 (C–Ar), 135.99 (C–Ar), 134.96 (C–Ar),
128.54 (CH–Ar), 128.22 (CH–Ar), 127.97 (CH–Ar),
125.70 (CH–Ar), 119.77 (CH–Ar), 67.22 (CH2), 51.21
(CH), 34.33 (C(CH3)3), 31.32 (C(CH3)3), 18.296 (CH3).
FTIR (neat): 3294 (w), 3264 (w), 1689 (s), 1661 (s). Mp:
85–88 ꢀC (methanol). HRMS (ES): calcd for C21H26N2O3:
355.2016 (M+H)+. Found: 355.2016.
4.1.2.5. 2-Phenyl-N-(1,2,3,4-tetrahydro-naphthalen-1-
yl)-acetamide (20). The title compound was obtained as
a white solid (16 mg, 59%). HPLC (method C): tR¼
10.36 min. Purity (ELSD): 100%. 1H NMR (400 MHz,
CDCl3): 7.33–7.04 (m, 9H, Ar–H), 5.63 (br s, 1H, NH),
5.20–5.15 (m, 1H, NHCH naphthyl), 3.62 (s, 2H, Ar–
CH2–CO), 2.74–2.72 (m, 2H, Ar–CH2 naphthyl), 2.07–2.00
(m, 1H, CH naphthyl), 1.82–1.63 (m, 3H, CH naphthyl).
13C NMR (75 MHz, CDCl3): 170.30 (C]O), 137.49 (C–
Ar), 136.54 (C–Ar), 134.86 (C–Ar), 129.28 (CH–Ar),
129.08 (CH–Ar), 128.96 (CH–Ar), 128.16 (CH–Ar),

E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
8865
127.28 (CH–Ar), 127.16 (CH–Ar), 126.17 (CH–Ar), 47.68
(CH), 43.99 (Ph–CH2), 30.17 (CH2), 29.14 (CH2), 20.12
(CH2). m/z (ESMS): 266 (M+H)+ (43%), 288 (M+Na)+
(100%). FTIR (neat): 3264 (m), 1631 (s). Mp: 124–125 ꢀC
(methanol). Anal. Calcd for C18H19NO: C: 81.48, H: 7.22,
N: 5.28. Found: C: 81.23, H: 7.22, N: 5.30.
127.9 (CH–Ar), 123.0 (CH–Ar), 121.8 (CH–Ar), 107.0
(CH–Ar), 70.7 (OCH2). m/z (EIMS): 235.13 (M+) (100%).
FTIR (neat): 1618 (m), 1225 (m), 1019 (m). Mp: 66–68 ꢀC
(ethanol). Anal. Calcd for C16H13NO: C: 81.68, H: 5.57,
N: 5.95. Found: C: 81.46, H: 5.63, N: 5.95.
4.1.5. Polymer-supported IIDQ (27). PS-quinoline (20 g,
2.74 mmol/g, 54.8 mmol, 1 equiv) was swollen in dry
DCM (200 mL). DIPEA (27 mL, 164 mmol, 3 equiv) was
added and the mixture was mechanically stirred and cooled
to 0 ꢀC. Isobutyl chloroformate (21.4 mL, 164 mmol,
3 equiv) was added dropwise to the reaction mixture. After
3 h, isobutanol (100 mL) was added, the mixture allowed
to warm to room temperature, and stirred mechanically for
16 h. The resin was then collected by filtration and washed
successively with three cycles of DCM, DCM/Et2O, Et2O
4.1.2.6. N-(1,2,3,4-Tetrahydro-naphthalen-1-yl)-benz-
amide (21). The title compound was obtained as a white
solid (18 mg, 67%). HPLC (method C): tR¼10.33 min. Pu-
rity (ELSD): 100%. 1H NMR (300 MHz, CDCl3): 7.78 (m,
2H, OC–C–CH), 7.52–7.12 (m, 7H, Ar–H), 6.38 (br s,
1H), 5.43–5.36 (m, 1H, NHCH naphthyl), 2.90–2.75 (m,
2H, Ar–CH2 naphthyl), 2.20–2.13 (m, 1H, CH naphthyl),
1.99–1.85 (m, 3H, CH naphthyl). 13C NMR (75 MHz,
CDCl3): 166.65 (C]O), 137.69 (C–Ar), 136.63 (C–Ar),
134.65 (C–Ar), 131.41 (CH–Ar), 129.22 (CH–Ar), 128.73
(CH–Ar), 128.52 (CH–Ar), 127.34 (CH–Ar), 126.90 (CH–
Ar), 126.32 (CH–Ar), 47.94 (CH), 30.18 (CH2), 29.26
(CH2), 20.05 (CH2). FTIR (neat): 3301 (m), 1632 (s). Mp:
122–125 ꢀC (ethanol). HRMS (ES): calcd for C17H17NO:
274.1202 (M+H)+. Found: 274.1206.
1
(200 mL each). H MAS-NMR (400 MHz, CDCl3): 7.80
(N–C–CH), 6.22 (N–CH–CH), 4.80 (OCH2–PS), 4.00
(CO2CH2), 3.32 (OCH2CH), 1.97 (CO2CH2CH(CH3)2),
1.74 (OCH2CH(CH3)2), 0.95 (CO2CH2CH(CH3)2), 0.83
(OCH2CH(CH3)2). FTIR (neat): 1709 (s), 1265 (s), 1018
(m). Determination of IIDQ loading. Phenylacetic acid
(765 mg, 5.62 mmol, 3 equiv) and benzylamine (614 mL,
5.62 mmol, 3 equiv) were dissolved in DCM (5 mL). PS-
IIDQ (maximum loading 1.87 mmol/g, 1.0 g, 1.87 mmol)
was added and the reaction mixture was shaken at room tem-
perature for 16 h. The resin was removed by filtration and
washed with DCM/MeOH (three cycles of 5 mL). The fil-
trates were combined and concentrated in vacuo. The residue
was taken up in EtOAc (50 mL), washed with 1 M HCl
(3ꢄ20 mL), 1 M NaHCO3 (3ꢄ20 mL), brine (1ꢄ20 mL),
dried over MgSO4, and concentrated in vacuo to give
2-phenyl-benzylacetamide as a white powder (370 mg,
88%). The yield of the reaction was related to the loading
of the resin (loading¼yieldꢄtheoretical loading¼0.88ꢄ
1.87¼1.68 mmol/g) and assumes no losses during the reac-
tion and its workup and thus represents the lower limit of
resin loading.
4.1.3. Polymer-supported quinoline (24). Merrifield resin
(25 g, Polymer Lab, 3.99 mmol/g, 99.8 mmol, 1 equiv)
was swollen in DMA (250 mL). K2CO3, (69 g, 499 mmol,
5 equiv), 6-hydroxyquinoline (36.2 g, 249 mmol, 2.5 equiv),
and a catalytic amount of KI were added and the reaction
mixture was heated at reflux with mechanical agitation for
6 h. The resin was collected by filtration and washed succes-
sively with THF/H2O (1/1, 3ꢄ250 mL), THF (3ꢄ250 mL),
DCM (3ꢄ250 mL), MeOH (3ꢄ250 mL), DCM (3ꢄ
250 mL), MeOH (3ꢄ250 mL), Et2O (3ꢄ250 mL). 1H
MAS-NMR+1H–1H COSY (400 MHz, CDCl3): 8.75 (N–
CH), 8.05–7.96 (N–CH–CH–CH and N–C–CH), 5.04
(OCH2). FTIR (neat): 1622 (w), 1223 (m), 1016 cmꢁ1 (w).
Loading of polymer-supported quinoline: determined by
nitrogen elemental analysis (C: 88.6, H: 7.18, N: 1.54, Cl:
0.20): 2.74 mmol/g (98%).
4.1.6. General procedure for using PS-IIDQ as coupling
reagent. To a solution of amine (1 equiv) and carboxylic
acid (1 equiv) in CH3CN was added PS-IIDQ (2 equiv).
The reaction mixture was shaken at room temperature for
24 h. The resin was then removed by filtration, and washed
with DCM/MeOH (three cycles). The filtrates were concen-
trated in vacuo and the unreacted amine and carboxylic acid
removed either by an aqueous workup (EtOAc, 1 M HCl,
1 M NaHCO3) or by using SPE cartridges containing a mixed
bed of acidic/basic MP ion-exchange resin (Polymer Lab,
500 mg).
4.1.4. 6-Benzyloxyquinoline (25). 6-Hydroxyquinoline
(5 g, 1 equiv, 34.4 mmol) was dissolved in DMF (30 mL).
K2CO3 (23.8 g, 5 equiv, 172 mmol) was introduced and
the reaction mixture was stirred for 1 h. Benzyl chloride
(4 mL, 1 equiv, 34.4 mmol) was added and the mixture
was stirred at 80 ꢀC for 24 h. DMF was evaporated under re-
duced pressure yielding a dark brown solid. This solid was
suspended in water (150 mL) and DCM (250 mL) and the in-
soluble impurities were filtered off. The water phase was ex-
tracted three times with DCM (50 mL). The combined
organic phases were washed with brine (100 mL), dried
over Na2SO4, and evaporated in vacuo. The brown solid ob-
tained was extracted with petroleum ether at 50 ꢀC. Evapo-
ration of the petroleum ether yielded 6-benzyloxyquinoline
as a pale yellow powder (3.78 g, 47%). HPLC (method B):
4.1.6.1. [1-(4-tert-Butyl-phenylcarbamoyl)-1-methyl-
ethyl]-carbamic acid tert-butyl ester (28). The title com-
pound was prepared according to the general procedure of
coupling with PS-IIDQ and obtained as a white solid
(62 mg, 69%). HPLC (method A): tR¼9.13 min. Purity
(ELSD): 100%. 1H NMR (250 MHz, CDCl3): 7.47–7.30 (m,
4H, Ar–H), 4.93 (br s, 1H, NH), 1.55 (s, 6H, C(CH3)2), 1.44
(s, 9H, Ar–C(CH3)3), 1.30 (s, 9H, OC(CH3)3). 13C NMR
(62.5 MHz, CDCl3): 172.55 (C]O), 155.27 (C]O),
146.93 (C–Ar), 135.54 (C–Ar), 125.72 (CH–Ar), 119.53
(CH–Ar), 80.27 (OC(CH3)3), 57.64 (NH–C(CH3)2), 34.32
(Ar–C(CH3)3), 31.35 (Ar–C(CH3)3), 28.25 (OC(CH3)3),
1
tR¼7.24 min. Purity (ELSD): 98%. H NMR (400 MHz,
CDCl3): 8.79 (dd, 1H, J¼4.4 Hz and 1.5 Hz, N–CH), 8.05
(dd, 1H, J¼8.1 Hz and 1.5 Hz, N–CH–CH–CH), 8.04 (d,
1H, J¼8.8 Hz, N–C–CH), 7.52–7.34 (m, 7H, Ar–H), 7.17
(d, 1H, J¼2.9 Hz, O–C–CH–C), 5.20 (s, 2H, OCH2). 13C
NMR (100 MHz, CDCl3): 157.3 (O–C–Ar), 148.5 (N–CH–
Ar), 144.9 (C–Ar), 136.9 (C–Ar), 135.3 (CH–Ar), 131.4
(CH–Ar), 129.7 (CH–Ar), 129.1 (C–Ar), 128.6 (CH–Ar),

8866
E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
25.73 (C(CH3)2). FTIR (neat): 3315 (m), 1686 (s), 1596 (m).
Mp: 148–151 ꢀC (methanol). HRMS (ES): calcd for
C19H30N2O3: 335.2329 (M+H)+. Found: 335.2328.
4.1.6.6. Aminoisobutyric acid methyl ester hydrochlo-
ride12 (33). To a solution of aminoisobutyric acid (5 g,
48.5 mmol, 1 equiv) in MeOH (50 mL) was added dropwise
at 0 ꢀC thionyl chloride (5.5 mL, 242 mmol, 5 equiv). After
completion of the addition, the solution was allowed to warm
up to room temperature and stirred for 5 h. The volatiles
were then evaporated in vacuo. The residue was taken up
in MeOH and crystallized upon addition of Et2O. The solid
collected by filtration, washed with Et2O, and dried in vacuo
to afford the title compound as white crystals (6.46 g, 87%).
1H NMR (300 MHz, DMSO-d6): 8.70 (br s, 2H, NH2), 3.76
(s, 3H, CH3), 1.63 (s, 6H, C(CH3)2). m/z (ESMS): 118
(M+H)+ (100%). Mp: 183–185 ꢀC (ethanol, lit.:28 185–
185.5 ꢀC).
4.1.6.2.
(1-Benzylcarbamoyl-1-methyl-ethyl)-carb-
amic acid tert-butyl ester (29). The title compound was pre-
pared according to the general procedure of coupling with
PS-IIDQ and obtained as a white solid (52 mg, 66%).
1
HPLC (method B): tR¼7.47 min. Purity (ELSD): 99%. H
NMR (300 MHz, CDCl3): 7.26–7.17 (m, 5H, Ar–H), 6.70
(br s, 1H, NH), 4.86 (br s, 1H), 4.37 (d, J¼5.4 Hz, 2H,
CH2), 1.44 (s, 6H, C(CH3)2), 1.33 (s, 9H, C(CH3)3). 13C
NMR (75 MHz, CDCl3): 174.45 (C]O), 154.69 (C]O),
138.36 (C–Ar), 128.57 (CH–Ar), 127.62 (CH–Ar), 127.29
(CH–Ar), 80.23 (OC(CH3)3), 56.83 (C(CH3)2), 43.69
(CH2), 28.23 (OC(CH3)3), 25.77 (C(CH3)2). FTIR (neat):
3350 (m), 3292 (m), 1682 (s), 1654 (s). Mp: 135–138 ꢀC
(methanol). HRMS (ES): calcd for C16H24N2O3: 293.1860
(M+H)+. Found: 293.1862.
4.1.6.7. (1,1-Dimethyl-2-morpholin-4-yl-2-oxo-ethyl)-
carbamic acid benzyl ester (34). The title compound was
prepared according to the general procedure of coupling
with PS-IIDQ and obtained as a white solid (40 mg, 44%).
HPLC (method B): tR¼7.918 min. Purity (ELSD): 100%.
1H NMR (250 MHz, CDCl3): 7.36–7.30 (m, 5H, Ar–H),
5.49 (br s, 1H, NH), 5.06 (s, 2H, Ar–CH2), 3.64–3.42 (m,
8H, CH2 morpholine), 1.52 (s, 6H, C(CH3)2). 13C NMR
(62.5 MHz, CDCl3): 171.17 (C]O), 154.18 (C]O),
136.20 (C–Ar), 128.47 (CH–Ar), 128.35 (CH–Ar), 128.27
(CH–Ar), 66.53 (CH2OCH2, Ar–CH2–O), 56.76 (C(CH3)2),
45.59 (N–CH2), 25.98 (C(CH3)2). FTIR (neat): 3306 (w),
3265 (m), 1714 (s), 1605 (s). Mp: 135–141 ꢀC (methanol).
HRMS (ES): calcd for C16H22N2O4: 307.1652 (M+H)+.
Found: 307.1650.
4.1.6.3.
(R)-(2-tert-Butoxycarbonylamino-2-methyl
propionylamino)-phenyl-acetic acid methyl ester (30).
The title compound was prepared according to the general
procedure of coupling with PS-IIDQ and obtained as a
white solid (60 mg, 64%). HPLC (method A): tR¼8.02 min.
1
Purity (ELSD): 100%. H NMR (300 MHz, CDCl3): 7.50
(br s, 1H, NH), 7.38–7.29 (m, 5H, Ar–H), 5.54 (d,
J¼7.2 Hz, 1H, CH), 4.92 (br s, 1H, NH), 3.71 (s, 3H,
CH3), 1.48 (d, J¼6.0 Hz, 6H, C(CH3)2), 1.39 (s, 9H,
C(CH3)3). 13C NMR (75 MHz, CDCl3): 173.96 (C]O),
171.27 (C]O), 154.64 (C]O), 136.57 (C–Ar), 128.82
(CH–Ar), 128.34 (CH–Ar), 127.17 (CH–Ar), 80.32
(OC(CH3)3), 56.75 (C(CH3)2), 56.52 (CH), 52.64 (OCH3),
28.18 (OC(CH3)3), 25.32 (C(CH3)2). FTIR (neat): 3320
(m), 1748 (m), 1684 (s), 1657 (s). Mp: 104–108 ꢀC (metha-
nol). HRMS (ES): calcd for C18H26N2O5: 351.1915
(M+H)+. Found: 351.1918.
4.1.6.8. [1-(Cyclohexylmethyl-carbamoyl)-1-methyl-
ethyl]-carbamic acid benzyl ester (35). The title compound
was prepared according to the general procedure of coupling
with PS-IIDQ and obtained as a white solid (58 mg, 61%).
HPLC (method C): tR¼10.32 min. Purity (ELSD): 100%.
1H NMR (400 MHz, CDCl3): 7.28–7.24 (m, 5H, Ar–H),
6.03 (s, 1H, NH), 5.26 (s, 1H, NH), 5.01 (s, 2H, Ar–CH2),
3.64 (m, 1H, CH), 1.74–0.99 (m, 10H, CH2 c-Hex), 1.43
(s, 6H, C(CH3)2). 13C NMR (100 MHz, CDCl3): 173.21
(C]O), 155.03 (C]O), 136.30 (C–Ar), 128.50 (CH–Ar),
128.15 (CH–Ar), 128.09 (CH–Ar), 66.66 (OCH2), 56.86
(C(CH3)2), 48.23 (CH), 32.77 (CH2), 25.69 (C(CH3)2),
25.52 (CH2), 24.66 (CH2). m/z (ESMS): 319 (M+H)+
(30%), 341 (M+Na)+ (100%). FTIR (neat): 3341 (w), 3296
(m), 1699 (s), 1649 (s). Mp: 121–122 ꢀC (methanol). Anal.
Calcd for C18H26N2O3: C: 67.90, H: 8.23, N: 8.79. Found:
C: 67.78, H: 8.28, N: 8.78.
4.1.6.4. (S)-Phenyl-phenylacetylamino-acetic acid
methyl ester (31). The title compound was prepared accord-
ing to the general procedure of coupling with PS-IIDQ and
obtained as a white solid (46 mg, 61%). HPLC (method B):
1
tR¼6.50 min. Purity (ELSD): 100%. H NMR (300 MHz,
CDCl3): 7.31–7.15 (m, 10H, Ar–H), 6.41 (d, J¼6.3 Hz,
1H, NH), 5.48 (d, J¼7.2 Hz, 1H, CH), 3.60 (s, 3H, CH3),
3.53 (s, 2H, CH2). 13C NMR (75 MHz, CDCl3): 171.18
(C]O), 170.21 (C]O), 136.32 (C–Ar), 134.39 (C–Ar),
129.31 (CH–Ar), 128.93 (CH–Ar), 128.87 (CH–Ar),
128.45 (CH–Ar), 127.36 (CH–Ar), 127.07 (CH–Ar), 56.40
(CH), 52.71 (OCH3), 43.39 (CH2). FTIR (neat): 3303 (m),
1740 (s), 1647 (s). Mp: 96–98 ꢀC (methanol). HRMS: calcd
for C17H17NO3: 284.1281 (M+H)+. Found: 284.1283.
4.1.6.9. 2-(2-Benzyloxycarbonylamino-2-methyl-pro-
pionylamino)-2-methyl-propionic acid methyl ester23
(36). The title compound was prepared according to the
general procedure of coupling with PS-IIDQ and obtained
as a white solid (67 mg, 67%). HPLC (method C):
4.1.6.5. (S)-Benzoylamino-phenyl-acetic acid methyl
ester22 (32). The title compound was prepared according
to the general procedure of coupling with PS-IIDQ and ob-
tained as a white solid (54 mg, 75%). HPLC (method C):
1
tR¼9.35 min. Purity (ELSD): 100%. H NMR (300 MHz,
CDCl3): 7.36–7.26 (m, 5H, Ar–H), 6.90 (br s, 1H, NH),
5.32 (br s, 1H, NH), 5.09 (s, 2H, CH2), 3.71 (s, 3H,
OCH3), 1.50 (s, 12H, C(CH3)2). m/z (ESMS): 337 (M+H)+
(20%), 359 (M+Na)+ (100%). Mp: 108–109 ꢀC (ethanol,
lit.:23 109–110 ꢀC).
1
tR¼9.38 min. Purity (ELSD): 100%. H NMR (250 MHz,
CDCl3): 7.85–7.80 (m, 2H, OC–C–CH), 7.55–7.30 (m, 8H,
Ar–H), 7.19 (br d, J¼6.3 Hz, 1H, NH), 5.78 (d, J¼7.2 Hz,
1H, CH), 3.77 (s, 3H, CH3). m/z (ESMS): 270 (M+H)+
(27%), 292 (M+Na)+ (100%). Mp: 104–105 ꢀC (ethanol,
lit.:22 104–105 ꢀC).
4.1.6.10. [1-Methyl-1-(1,2,3,4-tetrahydro-naphthalen-
1-ylcarbamoyl)-ethyl]-carbamic acid benzyl ester (38).

E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
8867
The title compound was prepared according to the general
procedure of coupling with PS-IIDQ and obtained as a white
solid (81 mg, 74%). HPLC (method C): tR¼10.63 min. Pu-
tR¼8.19 min. Purity (ELSD): 100%. FTIR (neat): 1740 (s),
1642 (s). HRMS (ES): calcd for C20H21NO3: 324.1594
(M+H)+. Found: 324.1592.
1
rity (ELSD): 100%. H NMR (300 MHz, CDCl3): 7.32–
7.08 (m, 9H, Ar–H), 6.40 (br d, J¼7.8 Hz, 1H, NH–CH),
5.34 (br s, 1H, NH), 5.14–5.09 (m, 1H, NHCH naphthyl),
5.07 (s, 2H, OCH2), 2.84–2.68 (m, 2H, Ar–CH2 naphthyl),
2.02–1.99 (m, 1H, CH naphthyl), 1.80–1.69 (m, 3H, CH
naphthyl), 1.55 (s, 6H, C(CH3)2). 13C NMR (75 MHz,
CDCl3): 173.42 (C]O), 154.85 (C]O), 137.59 (C–Ar),
136.62 (C–Ar), 136.14 (C–Ar), 129.09 (CH–Ar), 128.50
(CH–Ar), 128.150 (CH–Ar), 128.08 (CH–Ar), 127.17
(CH–Ar), 126.23 (CH–Ar), 66.71 (OCH2), 56.92
(C(CH3)2), 47.67 (CH), 30.00 (CH2), 29.23 (CH2), 25.53
(C(CH3)2), 20.04 (CH2). FTIR (neat): 3351 (w), 3286 (m),
1694 (s), 1645 (s). Mp: 119–121 ꢀC (ethanol). HRMS
(ES): calcd for C22H26N2O3: 367.2016 (M+H)+. Found:
367.2018.
4.1.6.15. N-Cyclohexylmethyl-benzamide26 (44). The
title compound was prepared according to the general proce-
dure of coupling with PS-IIDQ and obtained as a white solid
(51 mg, 84%). HPLC (method C): tR¼9.77 min. Purity
1
(ELSD): 100%. H NMR (300 MHz, CDCl3): 7.77–7.75
(m, 2H, OC–C–CH), 7.51–7.39 (m, 3H, OC–C–CH–CH–
CH), 6.09 (br s, 1H, NH), 4.05–3.92 (m, 1H, NHCH), 2.06–
2.01 (m, 2H, CH naphthyl), 1.80–1.59 (m, 3H, CH
naphthyl), 1.51–1.34 (m, 2H, CH naphthyl), 1.32–1.14 (m,
3H, CH naphthyl). m/z (ESMS): 204 (M+H)+ (100%). Mp:
152–154 ꢀC (ethanol, lit.:27 152–153 ꢀC).
4.1.6.16. 2-Benzoylamino-2-methyl-propionic acid
methyl ester (45). The title compound was prepared accord-
ing to the general procedure of coupling with PS-IIDQ and
obtained as a white solid (60 mg, 91%). HPLC (method
C): tR¼8.35 min. Purity (ELSD): 100%. 1H NMR
(400 MHz, CDCl3): 7.77 (d, J¼6.8 Hz, 2H, OC–C–CH),
7.51–7.39 (m, 3H, OC–C–CH–CH–CH), 6.81 (br s, 1H,
NH), 3.78 (s, 3H, OCH3), 1.68 (s, 6H, C(CH3)2). 13C
NMR (100 MHz, CDCl3): 175.86 (C]O), 166.57 (C]O),
134.51 (C–Ar), 131.50 (CH–Ar), 128.49 (CH–Ar), 126.91
(CH–Ar), 56.90 (C(CH3)2), 52.73 (OCH3), 24.74
(C(CH3)2). FTIR (neat): 3223 (m), 1732 (s), 1627 (s). Mp:
116–119 ꢀC (ethanol). HRMS (ES): calcd for C12H15NO3:
244.0944 (M+Na)+. Found: 244.0943.
4.1.6.11. (S)-1-(2-Benzyloxycarbonylamino-2-methyl-
propionyl)-pyrrolidine-2-carboxylic acid benzyl ester
(39). The title compound was prepared according to the gen-
eral procedure of coupling with PS-IIDQ, separated from the
carbamate by-product by column chromatography (hexane/
EtOAc 6/4), and was obtained as a colorless oil (4 mg, 3%).
In the case of amides derived from proline, the presence of
multiple rotamers24 made the NMR spectra poorly signifi-
cant to report. However, compound 63 was fully character-
ized using NMR at higher temperature. HPLC (method B):
tR¼6.32 min. Purity (ELSD): 100%. FTIR (neat): 3277
(m), 1739 (s), 1702 (s), 1621 (s). HRMS (ES): calcd for
C21H30N2O5: 391.2228 (M+H)+. Found: 391.2231.
4.1.6.17. (S)-1-Benzoyl-pyrrolidine-2-carboxylic acid
benzyl ester (47). The title compound was prepared
according to the general procedure of coupling with PS-
IIDQ, separated from the carbamate by-product by column
chromatography (hexane/EtOAc 6/4), and was obtained as
a colorless oil (26 mg, 34%). HPLC (method A): tR¼
7.88 min. Purity (ELSD): 100%. FTIR (neat): 1740 (s),
1629 (s). HRMS (ES): calcd for C19H19NO3: 310.1438
(M+Na)+. Found: 310.1434.
4.1.6.12.
N-Cyclohexylmethyl-2-phenyl-acetamide
(40). The title compound was prepared according to the gen-
eral procedure of coupling with PS-IIDQ and obtained as
a white solid (29 mg, 44%). HPLC (method C): tR¼
9.96 min. Purity (ELSD): 100%. 1H NMR (300 MHz,
CDCl3): 7.27–7.16 (m, 5H, Ar–H), 5.22 (br s, 1H, NH),
3.73–3.63 (m, 1H, CH), 3.46 (s, 2H, Ar–CH2), 1.79–0.88
(m, 10H, CH2 c-Hex). 13C NMR (75 MHz, CDCl3): 169.93
(C]O), 135.16 (C–Ar), 129.29 (CH–Ar), 128.89 (CH–Ar),
127.17 (CH–Ar), 48.12 (Ph–CH2), 43.96 (CH), 32.85 (CH2),
25.42 (CH2), 24.64 (CH2). FTIR (neat): 3267 (m), 1665 (s).
Mp: 125–127 ꢀC (methanol). HRMS (ES): calcd for
C14H19NO: 218.1540 (M+H)+. Found: 218.1540.
4.1.6.18. [(S)-1-(Cyclohexylmethyl-carbamoyl)-ethyl]-
carbamic acid benzyl ester (48). The title compound was
prepared according to the general procedure of coupling
with PS-IIDQ and obtained as a white solid (69 mg, 71%).
HPLC (method C): tR¼10.20 min. Purity (ELSD): 100%.
1H NMR (300 MHz, CDCl3): 7.26 (m, 5H, Ar–H), 5.96 (br
s, 1H, NH), 5.39 (br s, 1H, NH), 5.03 (s, 2H, Ar–CH2),
4.10 (m, 1H, CH*), 3.64 (m, 1H, CH c-Hex), 1.86–0.97
(m, 10H, CH2 c-Hex), 1.26 (d, J¼7.2 Hz, 3H, CH3). 13C
NMR (75 MHz, CDCl3): 171.18 (C]O), 155.92 (C]O),
136.21 (C–Ar), 128.49 (CH–Ar), 128.14 (CH–Ar), 127.96
(CH–Ar), 66.91 (OCH2), 50.62 (CH*), 48.23 (CH c-Hex),
32.85 (CH2), 25.43 (CH2), 24.69 (CH2), 18.76 (CH3).
FTIR (neat): 3277 (m), 1688 (s), 1642 (s). Mp: 153–
156 ꢀC (methanol). HRMS (ES): calcd for C17H24N2O3:
327.1679 (M+H)+. Found: 327.1677.
4.1.6.13.
2-Methyl-2-phenylacetylamino-propionic
acid methyl ester25 (41). The title compound was prepared
according to the general procedure of coupling with PS-
IIDQ and obtained as a white solid (51 mg, 73%). HPLC
1
(method C): tR¼8.66 min. Purity (ELSD): 100%. H NMR
(300 MHz, CDCl3): 7.31–7.19 (m, 5H, Ar–H), 5.93 (br s,
1H, NH), 3.64 (s, 3H, OCH3), 3.47 (s, 2H, CH2), 1.42 (6H,
C(CH3)2). m/z (ESMS): 236 (M+H)+ (33%), 258 (M+Na)+
(100%). Mp: 103–104 ꢀC (ethanol, lit.:25 102–103.5 ꢀC).
4.1.6.14. (S)-1-Phenylacetyl-pyrrolidine-2-carboxylic
acid benzyl ester (43). The title compound was prepared
according to the general procedure of coupling with PS-
IIDQ, separated from the carbamate by-product by column
chromatography (hexane/EtOAc 6/4), and was obtained
as a colorless oil (52 mg, 60%). HPLC (method A):
4.1.6.19. 2-((S)-2-Benzyloxycarbonylamino-propionyl-
amino)-2-methyl-propionic acid methyl ester28 (49).
The title compound was prepared according to the general
procedure of coupling with PS-IIDQ and obtained as a white
solid (79 mg, 82%). HPLC (method C): tR¼9.24 min. Purity

8868
E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
(ELSD): 100%. 1H NMR (300 MHz, CDCl3): 7.34–7.29 (m,
5H, Ar–H), 6.725 (br s, 1H, NH), 5.44 (br s, 1H, NH), 5.10 (s,
2H, CH2), 4.24–4.20 (m, 1H, CH), 3.70 (s, 3H, OCH3), 1.50
(d, J¼3 Hz, 6H, C(CH3)2), 1.35 (d, J¼7 Hz, 3H, CH–CH3).
m/z (ESMS): 345 (M+Na)+ (100%). Mp: 118–120 ꢀC (etha-
nol, lit.:28 120 ꢀC).
52.69 (OCH3), 24.67 (C(CH3)2). m/z (ESMS): 252 (M+H)+
(22%), 274 (M+Na)+ (100%). FTIR (neat): 3209 (w), 1738
(s), 1649 (s). Mp: 61–62 ꢀC (methanol). Anal. Calcd for
C13H17NO4: C: 62.14, H: 6.82, N: 5.57. Found: C: 61.98,
H: 6.85, N: 5.52.
4.1.6.24. 2-Phenoxy-N-(1,2,3,4-tetrahydro-naphtha-
len-1-yl)-acetamide (56). The title compound was prepared
according to the general procedure of coupling with PS-
IIDQ and obtained as a white solid (62 mg, 74%). HPLC
(method C): tR¼10.76 min. Purity (ELSD): 100%. 1H
NMR (400 MHz, CDCl3): 7.31 (t, J¼8.8 Hz, 2H, O–C–
CH–CH), 7.22–7.10 (m, 4H, Ar–H naphthyl), 7.02 (t, J¼
7.2 Hz, 1H, O–C–CH–CH–CH), 6.90 (d, J¼8.0 Hz, 2H,
O–C–CH), 6.79 (d, J¼7.6 Hz, 1H, NH), 5.32–5.28 (m, 1H,
NHCH), 4.57 (AB-d, J¼14.8 Hz, 2H, OCH2), 2.87–2.74
(m, 2H, Ar–CH2 naphthyl), 2.14–2.09 (m, 1H, CH naph-
thyl), 1.87–1.77 (m, 3H, CH naphthyl). 13C NMR
(75 MHz, CDCl3): 167.60 (C]O), 157.10 (C–Ar), 137.58
(C–Ar), 136.15 (C–Ar), 129.70 (CH–Ar), 129.18 (CH–Ar),
128.36 (CH–Ar), 127.33 (CH–Ar), 126.28 (CH–Ar),
122.08 (CH–Ar), 114.67 (CH–Ar), 67.38 (OCH2), 47.20
(CH), 30.23 (CH2), 29.16 (CH2), 20.11 (CH2). m/z
(ESMS): 304 (M+Na)+ (100%). FTIR (neat): 3309 (m),
1649 (s). Mp: 79–82 ꢀC (ethanol). Anal. Calcd for
C18H19NO2: C: 76.84, H: 6.81, N: 4.98. Found: C: 76.69,
H: 6.81, N: 4.97.
4.1.6.20. (S)-((S)-2-Benzyloxycarbonylamino-propio-
nylamino)-phenyl-acetic acid methyl ester (51). The title
compound was prepared according to the general procedure
of coupling with PS-IIDQ and obtained as a white solid
(92 mg, 83%). HPLC (method C): tR¼9.76 min. Purity
(ELSD): 100%. 1H NMR (300 MHz, CDCl3): 7.32 (m, 10H,
Ar–H), 7.19 (br s, 1H, NH), 5.54 (d, J¼7.2 Hz, 1H, CH–Ph),
5.40 (br s, 1H, NH), 5.07 (s, 2H, Ar–CH2), 4.33 (m, 1H, CH–
CH3), 3.71 (s, 3H, OCH3), 1.38 (d, J¼6.9 Hz, 3H, CH–CH3).
13C NMR (75 MHz, CDCl3): 171.69 (C]O), 171.05
(C]O), 155.93 (C]O), 136.17 (C–Ar), 136.11 (C–Ar),
128.99 (CH–Ar), 128.60 (CH–Ar), 128.53 (CH–Ar),
128.17 (CH–Ar), 128.06 (CH–Ar), 127.21 (CH–Ar), 67.03
(OCH2), 56.49 (CH–Ph), 52.82 (OCH3), 50.35 (CHCH3),
18.61 (CH3). FTIR (neat): 3301 (m), 1734 (s), 1692 (s),
1650 (s). Mp: 121–123 ꢀC (methanol). HRMS (ES): calcd
for C20H22N2O5: 371.1602 (M+H)+. Found: 371.1601.
4.1.6.21. 4-Phenoxyacetyl-morpholine29 (52). The title
compound was prepared according to the general procedure
of coupling with PS-IIDQ and obtained as a white solid
(53 mg, 80%). HPLC (method C): tR¼8.21 min. Purity
4.1.6.25.
N-(4-tert-Butyl-phenyl)-2-phenoxy-acet-
1
(ELSD): 100%. H NMR (300 MHz, CDCl3): 7.32–7.27
amide (57). The title compound was prepared according to
thegeneral procedure of coupling with PS-IIDQ and obtained
as a white solid (70 mg, 83%). HPLC (method C): tR¼
11.09 min. Purity (ELSD): 100%. 1H NMR (300 MHz,
CDCl3): 8.25 (br s, 1H, NH), 7.53–7.50 (m, 2H, HN–C–
CH), 7.40–7.33 (m, 2H, HN–C–CH–CH, 2H, O–C–CH–
CH), 7.09–6.99 (m, 3H, O–C–CH–CH–CH), 4.61 (s, 2H,
CH2), 1.33 (s, 9H, C(CH3)3). 13C NMR (75 MHz, CDCl3):
166.15 (C]O), 157.03 (C–Ar), 147.86 (C–Ar), 134.14 (C–
Ar), 129.84 (CH–Ar), 125.85 (CH–Ar), 122.37 (CH–Ar),
119.95 (CH–Ar), 114.82 (CH–Ar), 67.62 (OCH2), 34.37
(C(CH3)3), 31.30 (C(CH3)3). m/z (ESMS): 306 (M+Na)+
(47%), 589 (2M+Na)+ (100%). FTIR (neat): 3264 (w), 1657
(s). Mp: 80–82 ꢀC (methanol). Anal. Calcd for C18H21NO2:
C: 76.30, H: 7.47, N: 4.94. Found: C: 76.09, H: 7.50, N: 4.97.
(m, 2H, O–C–CH–CH), 7.02–6.93 (m, 3H, O–C–CH–CH–
CH), 4.69 (s, 2H, Ar–O–CH2), 3.64 (m, 8H, CH2 morpho-
line). m/z (ESMS): 222 (M+H)+ (23%), 244 (M+Na)+
(100%). Mp: 95–97 ꢀC (ethanol, lit.:29 94–96 ꢀC).
4.1.6.22. N-Cyclohexylmethyl-2-phenoxy-acetamide
(53). The title compound was prepared according to the
general procedure of coupling with PS-IIDQ and obtained
as a white solid (36 mg, 52%). HPLC (method C):
1
tR¼10.36 min. Purity (ELSD): 100%. H NMR (300 MHz,
CDCl3): 7.34–7.29 (m, 2H, O–C–CH–CH), 7.02 (t,
J¼7.5 Hz, 1H, O–C–CH–CH–CH), 6.91 (d, J¼7.8 Hz, 2H,
O–C–CH), 6.45 (br s, 1H, NH), 4.46 (s, 2H, Ar–O–CH2),
3.92–3.82 (m, 1H, CH), 1.95–1.10 (4m, 10H, CH2 c-Hex).
13C NMR (75 MHz, CDCl3): 167.150 (C]O), 157.22 (C–
Ar), 129.72 (CH–Ar), 122.06 (CH–Ar), 114.70 (CH–Ar),
67.44 (OCH2), 47.78 (CH), 32.95 (CH2), 25.42 (CH2),
24.74 (CH2). FTIR (neat): 3335 (m), 1647 (s). Mp: 75–
78 ꢀC (methanol). HRMS (ES): calcd for C14H19NO2:
256.1308 (M+Na)+. Found: 256.1305.
4.1.6.26. N-Benzyl-2-phenoxy-acetamide30 (58). The
title compound was prepared according to the general proce-
dure of coupling with PS–IIDQ and obtained as a white solid
(59 mg, 82%). HPLC (method C): tR¼9.85 min. Purity
(ELSD): 100%. 1H NMR (300 MHz, CDCl3): 7.36–7.25 (m,
7H, Ar–H), 7.04 (t, J¼7.5 Hz, 1H, O–C–CH–CH–CH), 6.90
(d, J¼7.5 Hz, 2H, O–C–CH), 4.54 (d, J¼5.7 Hz, 2H,
NHCH2), 4.46 (s, 2H, OCH2). m/z (ESMS): 242 (M+H)+
(22%), 264 (M+Na)+ (100%). Mp: 84–85 ꢀC (ethanol,
lit.:31 84–86 ꢀC).
4.1.6.23. 2-Methyl-2-(2-phenoxy-acetylamino)-pro-
pionic acid methyl ester (54). The title compound was pre-
pared according to the general procedure of coupling with
PS-IIDQ and obtained as a white solid (53 mg, 70%).
HPLC (method C): tR¼9.14 min. Purity (ELSD): 100%.
1H NMR (300 MHz, CDCl3): 7.32 (t, J¼7.5 Hz, 2H, O–C–
CH–CH), 7.15 (br s, 1H, NH), 7.02 (t, J¼7.5 Hz, 1H, O–
C–CH–CH–CH), 6.94 (d, J¼7.8 Hz, 2H, O–C–CH), 4.44
(s, 2H, CH2), 3.76 (s, 3H, OCH3), 1.60 (s, 6H, C(CH3)2).
13C NMR (75 MHz, CDCl3): 174.64 (C]O), 167.47
(C]O), 157.19 (C–Ar), 129.70 (CH–Ar), 122.09 (CH–
Ar), 114.76 (CH–Ar), 67.49 (OCH2), 56.40 (C(CH3)2),
4.1.6.27. (S)-(2-Phenoxy-acetylamino)-phenyl-acetic
acid methyl ester32 (59). The title compound was prepared
according to the general procedure of coupling with PS-
IIDQ and obtained as a white solid (73 mg, 82%). HPLC
1
(method C): tR¼9.94 min. Purity (ELSD): 99%. H NMR
(300 MHz, CDCl3): 7.58 (d, J¼6.6 Hz, 1H, NH), 7.37–
7.29 (m, 7H, Ar–H), 7.06–7.01 (m, 1H, O–C–CH–CH–

E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
8869
CH), 6.97–6.92 (m, 2H, O–C–CH), 5.67 (d, J¼7.5 Hz, 1H,
CH), 4.53 (AB-d, J¼15 Hz, 2H, CH2), 3.74 (s, 3H, CH3).
m/z (ESMS): 300 (M+H)+ (19%), 322 (M+Na)+ (100%).
Mp: 94–96 ꢀC (ethanol, lit.:32 95–96 ꢀC).
PS-IIDQ, separated from the carbamate by-product by col-
umn chromatography (petroleum ether/EtOAc 6/4), and ob-
tained as a pale yellow oil (54 mg, 50%). HPLC (method A):
tR¼9.19 min. Purity (ELSD): 100%. FTIR (neat): 1740 (s),
1645 (s). HRMS: calcd for C26H25NO3: 400.1907 (M+H)+.
Found: 400.1905.
4.1.6.28. (S)-Pyrrolidine-1,2-dicarboxylic acid 2-
benzyl ester 1-isobutyl ester (63). Isobutylchloroformate
(54 mL, 0.41 mmol, 1 equiv) was added to a mixture of pro-
line benzyl ester hydrochloride (100 mg, 0.41 mmol,
1 equiv) and DIPEA (137 mL, 0.82 mmol, 2 equiv) in
DCM (10 mL). The mixture was stirred at room temperature
for 2 h and concentrated in vacuo. The residue was taken up
in EtOAc (50 mL) and washed with 1 M NaHCO3 (3ꢄ
25 mL), 1 M HCl (3ꢄ25 mL), brine (1ꢄ25 mL), dried
over MgSO4, filtered, and concentrated in vacuo to give
the title compound as a pale yellow oil (109 mg, 85%).
HPLC (method A): tR¼9.02 min. Purity (ELSD): 100%.
1H NMR (400 MHz, 373 K, DMSO-d6): 7.38–7.33 (m,
5H, Ar–H), 5.15 (s, 2H, Ar–CH2), 4.34 (dd, J¼3.5 Hz and
8.5 Hz, 1H, CH*), 3.78 (d, J¼6.4 Hz, 2H, OCH2CH), 3.44
(m, 2H, N–CH2), 2.26 (m, 1H, CH(CH3)2), 1.94–1.84 (m,
4H, CH*CH2CH2), 0.87 (d, J¼6.75 Hz, 6H, CH(CH3)2).
13C NMR (100 MHz, 363 K, DMSO-d6): 172.01 (C]O),
154.00 (C]O), 135.9 (C–Ar), 128.23 (CH–Ar), 127.84
(CH–Ar), 127.56 (CH–Ar), 70.60 (Ph–CH2), 65.85
(OCH2CH), 58.75 (CH*), 46.28 (CH2), 29.80 (CH2), 27.44
(CH(CH3)2), 23.28 (CH2), 18.56 (CH(CH3)2). FTIR (neat):
1745 (m), 1702 (s). HRMS (ES): calcd for C17H23NO4:
306.1700 (M+H)+. Found: 306.1699.
4.1.6.33. (S)-1-[1-(4-Chloro-phenyl)-cyclopropanecar-
bonyl]-pyrrolidine-2-carboxylic acid benzyl ester (68).
The title compound was prepared according to the general
procedure of coupling with PS-IIDQ, separated from the
carbamate by-product by column chromatography (petro-
leum ether/EtOAc 6/4), and obtained as a pale yellow oil
(44 mg, 43%). HPLC (method A): tR¼9.31 min. Purity
(ELSD): 96%. FTIR (neat): 1740 (s), 1637 (s). HRMS: calcd
for C22H22NO3Cl: 384.1361 (M+H)+. Found: 284.1362.
4.1.6.34. (S)-1-(2-Cyclohexyl-acetyl)-pyrrolidine-2-
carboxylic acid benzyl ester (69). The title compound
was prepared according to the general procedure of coupling
with PS-IIDQ, separated from the carbamate by-product by
column chromatography (petroleum ether/EtOAc 6/4), and
obtained as a pale yellow oil (58 mg, 66%). HPLC (method
A): tR¼9.26 min. Purity (ELSD): 100%. FTIR (neat): 1742
(s), 1642 (s). HRMS: calcd for C20H27NO3: 330.2064
(M+H)+. Found: 330.2062.
4.1.6.35.
(S)-1-(2-Adamantan-1-yl-acetyl)-pyrrol-
idine-2-carboxylic acid benzyl ester (70). The title com-
pound was prepared according to the general procedure of
coupling with PS-IIDQ, separated from the carbamate by-
product by column chromatography (petroleum ether/
EtOAc 6/4), and obtained as a pale yellow oil (49 mg,
48%). HPLC (method A): tR¼10.10 min. Purity (ELSD):
100%. FTIR (neat): 1742 (s), 1638 (s). HRMS: calcd for
C24H31NO3: 382.2382 (M+H)+. Found: 382.2383.
4.1.6.29. (S)-1-(3,3-Diphenyl-propionyl)-pyrrolidine-
2-carboxylic acid benzyl ester (64). The title compound
was prepared according to the general procedure of coupling
with PS-IIDQ, separated from the carbamate by-product by
column chromatography (petroleum ether/EtOAc 6/4), and
obtained as a pale yellow oil (48 mg, 43%). HPLC (method
A): tR¼9.44 min. Purity (ELSD): 94%. FTIR (neat): 1740
(s), 1645 (s). HRMS (ES): calcd for C27H27NO3: 414.1907
(M+H)+. Found: 414.1905.
4.1.6.36. (S)-1-(3-Phenyl-butyryl)-pyrrolidine-2-carb-
oxylic acid benzyl ester (71). The title compound was pre-
pared according to the general procedure of coupling with
PS-IIDQ, separated from the carbamate by-product by col-
umn chromatography (petroleum ether/EtOAc 6/4), and ob-
tained as a pale yellow oil (54 mg, 57%). HPLC (method B):
tR¼7.14 min. Purity (ELSD): 100%. FTIR (neat): 1742 (s),
1644 (s). HRMS (ES): calcd for C22H25NO3: 374.1726
(M+Na)+. Found: 374.1728.
4.1.6.30.
(S)-1-(3-Phenyl-propionyl)-pyrrolidine-2-
carboxylic acid benzyl ester33 (65). The title compound
was prepared according to the general procedure of coupling
with PS-IIDQ, separated from the carbamate by-product by
column chromatography (petroleum ether/EtOAc 6/4), and
obtained as a pale yellow oil (69 mg, 76%). HPLC (method
A): tR¼8.72 min. Purity (ELSD): 100%. FTIR (neat): 3222
(w), 1739 (s), 1642 (s). HRMS (ES): calcd for
C21H23NO3: 338.1751 (M+H)+. Found: 338.1758.
4.1.6.37.
(S)-1-(2-Phenyl-propionyl)-pyrrolidine-2-
carboxylic acid benzyl ester (72). The title compound
was prepared according to the general procedure of coupling
with PS-IIDQ, separated from the carbamate by-product by
column chromatography (petroleum ether/EtOAc 6/4), and
obtained as a pale yellow oil (32 mg, 35%). HPLC (method
B): tR¼7.11 min. Purity (ELSD): 99%. FTIR (neat): 1742
(s), 1644 (s). HRMS (ES): calcd for C21H23NO3: 338.1751
(M+H)+. Found: 338.1748.
4.1.6.31.
(S)-1-(3,3,3-Triphenyl-propionyl)-pyrrol-
idine-2-carboxylic acid benzyl ester (66). The title com-
pound was prepared according to the general procedure of
coupling with PS-IIDQ, separated from the carbamate by-
product by column chromatography (petroleum ether/EtOAc
6/4), and obtained as a pale yellow oil (24 mg, 18%). HPLC
(method B): tR¼8.22 min. Purity (ELSD): 100%. FTIR
(neat): 3218 (w), 1738 (s), 1643 (s). HRMS (ES): calcd for
C33H31NO3: 490.2377 (M+H)+. Found: 490.2385.
4.1.6.38. (S)-1-Cyclohexanecarbonyl-pyrrolidine-2-
carboxylic acid benzyl ester34 (73). The title compound
was prepared according to the general procedure of coupling
with PS-IIDQ, separated from the carbamate by-product by
column chromatography (petroleum ether/EtOAc 6/4), and
obtained as a pale yellow oil (25 mg, 30%). HPLC (method
4.1.6.32. (S)-1-Diphenylacetyl-pyrrolidine-2-carboxy-
lic acid benzyl ester (67). The title compound was prepared
according to the general procedure of coupling with

8870
E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
A): tR¼8.80 min. Purity (ELSD): 100%. FTIR (neat): 1741
(s), 1639 (s). HRMS (ES): calcd for C19H25NO3: 316.1907
(M+H)+. Found: 316.1910.
References and notes
1. (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1
2000, 3815–4195; (b) Kirschning, A.; Monenschein, H.;
Wittenberg, R. Angew. Chem., Int. Ed. 2001, 40, 650–679; (c)
Bhalay, G.; Dunstan, A.; Glen, A. Synlett 2000, 1846–1859.
2. See for example: Desai, M. C.; Stephens Stramiello, L. M.
Tetrahedron Lett. 1993, 34, 7685–7688.
3. See for example: Zhang, M.; Vedantham, P.; Flynn, D. L.;
Hanson, P. R. J. Org. Chem. 2004, 69, 8340–8344.
4. Chinchilla, R.; Dodsworth, D. J.; Najera, C.; Soriano, J. M.
Tetrahedron Lett. 2000, 41, 2463–2466.
4.1.6.39. (S)-1-Cyclopentanecarbonyl-pyrrolidine-2-
carboxylic acid benzyl ester (74). The title compound
was prepared according to the general procedure of coupling
with PS-IIDQ, separated from the carbamate by-product by
column chromatography (petroleum ether/EtOAc 6/4), and
obtained as a pale yellow oil (44 mg, 55%). HPLC (method
A): tR¼8.42 min. Purity (ELSD): 100%. FTIR (neat): 1741
(s), 1639 (s). HRMS (ES): calcd for C18H23NO3: 302.1751
(M+H)+. Found: 302.1746.
4.1.6.40. Boc-Pro–Pro-OBn24 (75). The title compound
was prepared according to the general procedure of coupling
with PS-IIDQ, separated from the carbamate by-product by
column chromatography (petroleum ether/EtOAc 6/4), and
obtained as a pale yellow oil (53 mg, 49%). HPLC (method
A): tR¼8.46 min. Purity (ELSD): 100%. FTIR (neat): 3222
(w), 1741 (m), 1693 (s), 1656 (s). HRMS (ES): calcd for
C22H30N2O5: 403.2228 (M+H)+. Found: 403.2229.
5. Filip, S. V.; Lejeune, V.; Vors, J.-P.; Martinez, J.; Cavelier, F.
Eur. J. Org. Chem. 2004, 9, 1936–1939.
6. Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397–4398.
7. (a) Albericio, F.; Bofill, J. M.; El-Faham, A.; Kates, S. A.
J. Org. Chem. 1998, 63, 9678–9683; (b) Albericio, F.; Cases,
M.; Alsina, J.; Triolo, S. A.; Carpino, L. A.; Kates, S. A.
Tetrahedron Lett. 1997, 38, 4853–4856.
8. Tung, R. D.; Rich, D. H. J. Am. Chem. Soc. 1985, 107, 4342–
4343.
4.1.7. Z-Gly-L-Phe-Val-OMe23 (76). To a solution of H-
Val-OMe hydrochloride (29 mg, 0.175 mmol, 1 equiv), DI-
PEA (29 mL, 0.175 mmol, 1 equiv), and Z-Gly–Phe-OH
(60 mg, 0.175 mmol, 1 equiv) in CH3CN (5 mL) was added
PS-IIDQ (250 mg, 0.350 mmol, 2 equiv). The reaction mix-
ture was shaken at room temperature for 24 h, filtered and
the resin washed with DCM/MeOH (three cycles of 5 mL).
The filtrates were concentrated in vacuo and the unreacted
amine and carboxylic acid removed using an SPE cartridge
containing a mixed bed of acidic/basic MP ion-exchange
resin (Polymer Lab, 500 mg). The title compound was ob-
tained as a pale yellow oil (82 mg, 65%). HPLC (method
B): tR¼8.25 min. Purity (ELSD): 100%. 1H NMR
(300 MHz, CDCl3): 7.27–7.09 (m, 10H, Ar–H), 6.76 (br s,
1H), 6.40 (br s, 1H), 5.42 (br s, 1H), 5.03 (s, 2H, Ph–CH2–
O), 4.66–4.63 (m, 1H, CH*Phe), 4.34 (dd, J¼
8.4 Hz and 5.2 Hz, 1H, CH*Val), 3.77 (m, 2H, NH–CH2),
3.60 (s, 3H, OCH3), 2.97 (d, J¼4.4 Hz, 2H, CHCH2Ph),
2.02–1.96 (m, 1H, CH(CH3)2), 0.77 (d, J¼6.8 Hz, 3H, CH3),
0.74 (d, J¼6.8 Hz, 3H, CH3). m/z (ESMS): 470 (M+H)+
(5%), 492 (M+Na)+ (100%).
9. (a) Belleau, B.; Martel, R.; Lacasse, G.; Menard, M.;
Weinberg, N. L.; Perron, Y. G. J. Am. Chem. Soc. 1968,
90, 823–824; (b) Belleau, B.; Malek, G. J. Am. Chem.
Soc. 1968, 90, 1651–1652.
10. Valeur, E.; Bradley, M. Chem. Commun. 2005, 1164–1166.
11. Delgado, M.; Janda, K. D. Curr. Org. Chem. 2002, 6, 1031–1043.
12. Boissonnas, R. A.; Guttmann, S.; Jaquenoud, P. A.; Waller, J. P.
Helv. Chim. Acta 1955, 38, 1491–1501.
13. Van der Auwera, C.; Van Damme, S.; Anteunis, M. J. O. Int. J.
Pept. Protein Res. 1987, 29, 464–471.
14. PS-IIDQ is now commercially available from Novabiochem
(01-64-0469) and Polymer Laboratories (PL-IIDQ).
15. Perreux, L.; Loupy, A.; Volatron, F. Tetrahedron 2002, 58,
2155–2162.
16. Heyde, C.; Zug, I.; Hartmann, H. Eur. J. Org. Chem. 2000,
3273–3278.
17. Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101–1104.
18. Acheson, R. M.; Harvey, C. W. C. J. Chem. Soc., Perkin
Trans. 1 1976, 465–470.
19. Park, S.-D.; Oh, J.-H.; Lim, D. Tetrahedron Lett. 2002, 43,
6309–6311.
20. Badr, M. Z. A.; Aly, M. M.; Mahgoub, S. A.; Fahmy, A. M.;
Atallah, A. A. Bull. Chem. Soc. Jpn. 1988, 61, 1779–1783.
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523–528.
22. Dondoni, A.;Perrone,D.;Semola, T. Synthesis1995, 2, 181–186.
23. Albericio, F.; Bailen, M. A.; Chinchilla, R.; Dodsworth, D. J.;
Najera, C. Tetrahedron 2001, 57, 9607–9613.
24. Zhang, R.; Madalengoita, J. S. Tetrahedron Lett. 1996, 37,
6235–6239.
25. Obrecht, D.; Heimgartner, H. Helv. Chim. Acta 1987, 70,
102–115.
4.1.8. Z-Gly-D-Phe-Val-OMe23 (77). The title compound
was prepared similar to compound 76 and obtained as a
pale yellow oil (78 mg, 63%). HPLC (method B): tR¼
8.26 min. Purity(ELSD):100%. 1HNMR(300 MHz,CDCl3):
7.29–7.12 (m, 10H), 6.64 (br s, 1H), 6.28 (br s, 1H), 5.34 (br s,
1H), 5.05 (s, 2H, Ph–CH2–O), 4.68–4.62 (m, 1H, CH*Phe),
4.36 (dd, J¼8.4 Hz and 5.2 Hz, 1H, CH*Val), 3.79 (m, 2H,
NHCH2), 3.63 (s, 3H, OCH3), 3.05–2.95 (m, 2H, CHCH2Ph),
2.06–1.98 (m, 1H, CH(CH3)2), 0.79 (d, J¼6.8 Hz, 3H, CH3),
0.76 (d, J¼6.8 Hz, 3H, CH3). m/z (ESMS): 470 (M+H)+
(5%), 492 (M+Na)+ (100%).
26. Wintner, E. A.; Conn, M. M.; Rebek, J., Jr. J. Am. Chem. Soc.
1994, 116, 8877–8884.
Acknowledgements
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1219–1227.
The authors are grateful to Astra Zeneca, Eli Lilly, Evotec
OAI, GSK, and Pfizer for financial support of the Combina-
torial Centre of Excellence.
28. Wipf, P.; Heimgartner, H. Helv. Chim. Acta 1987, 70, 354–368.
29. Ogawa, T.; Hikasa, T.; Ikegami, T.; Ono, N.; Suzuki, H.
J. Chem. Soc., Perkin Trans. 1 1994, 3473–3478.

E. Valeur, M. Bradley / Tetrahedron 63 (2007) 8855–8871
8871
30. Koh, H. J.; Kim, T. H.; Lee, B.-S.; Lee, I. J. Chem. Res. 1996,
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33. Abraham, D. J.; Gazze, D. M.; Kennedy, P. E.; Mokotoff, M.
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