A novel purification method in organic synthesis using hydrogen bonding

Article abstract of DOI:10.1002/ejoc.200700242

A new workup and purification method based on quadruple hydrogen-bonding interactions is reported. Substrates containing a hydrogen-bonding affinity tag - either directly connected or through a cleavable linker - were conveniently separated from a reactio

Full text of DOI:10.1002/ejoc.200700242

FULL PAPER
DOI: 10.1002/ejoc.200700242
A Novel Purification Method in Organic Synthesis Using Hydrogen Bonding
Bas W. T. Gruijters,[a] Jorge M. M. Verkade,[a] Floris L. van Delft,[a] Rint P. Sijbesma,[b]
Pedro H. H. Hermkens,[c] and Floris P. J. T. Rutjes*[a]
Keywords: Affinity separation / Hydrogen bonding / Ureidopyrimidinone / Parallel synthesis / Non-covalent linking
A new workup and purification method based on quadruple
hydrogen-bonding interactions is reported. Substrates con-
taining a hydrogen-bonding affinity tag – either directly con-
nected or through a cleavable linker – were conveniently
separated from a reaction mixture and purified using a resin
containing self-complementary affinity tags. Several Ugi
products and nucleophilic aromatic substitution products
were successfully purified by this hydrogen-bonding-based
affinity-separation protocol.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
to transfer of the tagged compounds to the affinity me-
dium, while other reactants will remain in the initial phase.
Affinity separation has been recognized as a welcome tool
in organic synthesis, and has been explored by different
groups in recent years.[5] A range of suitable tags has been
developed, utilising all kinds of affinity interactions, such
as for example fluorous interactions,[6,7] hydrophobic inter-
actions,[8–10] ionic interactions between crown ethers and
ammonium ions,[11,12] metal chelation between diacid moie-
ties and CuII ions,[13,14] and a combination of fluorous in-
teractions and hydrogen bonding.[15] A first example of pu-
rification solely by hydrogen bonding was developed by Fu-
kase and co-workers.[16,17] They used the host–guest interac-
tion of bis(2,6-diamidopyridine)amide of isophthalic acid
and barbituric acid, which form a strong complex through
the formation of six hydrogen bonds.[18] The binding con-
stant of the complex (2.8ϫ104 –1), however, is too small
to bind all types of tagged products.[19] We aimed to explore
the possibilities of the latter affinity purification method
using the robust self-complementary hydrogen bonding ure-
ideopyrimidinone (UPy) unit (Figure 1), which displays sig-
nificantly larger binding constants (UPy dimerization con-
stant is 6ϫ107 –1 in chloroform, 6ϫ108 –1 in toluene)[20]
and therefore might be more widely applicable.
In a previous account, we already demonstrated the via-
bility of a similar hydrogen-bonding-based affinity-separa-
tion strategy for catalyst recycling.[21] We envisioned that
the same affinity separation might be used in a synthetic
sense, where a substrate connected to a UPy affinity tag
(AT) can undergo modification in solution phase (Fig-
ure 1). The UPy moiety forms dimers by generating four
hydrogen bonds in apolar solvents, and dissociates again in
polar solvents.[22] Hence, subsequent treatment with a resin
containing a self-complementary UPy affinity unit (viz. 1)
will lead to the corresponding dimeric complex. After wash-
ing of the complex and transfer to a polar solvent, the hy-
Introduction
The ever increasing demand of the pharmaceutical in-
dustry for small drug-like organic molecules has resulted in
the development of a range of synthetic tools, which con-
tribute to the speed, efficiency and selectivity of synthesis
routes.[1] An important aspect therein is the ability to sepa-
rate the desired products from side-products and impurities.
Therefore, not only new efficient chemical transformations
have to be developed, but novel, broadly applicable purifi-
cation protocols as well.
A disadvantage of solution-phase synthesis is the fact
that reactions are labour-intensive in terms of workup and
purification of products. Another drawback of the aqueous
workup and purification is that these operations are not
easily automated, rendering solution-phase synthesis in
principle less suited for automated library synthesis. These
drawbacks of solution-phase synthesis for pharmaceutical
purposes led to the development of robust alternatives such
as solid-phase synthesis.[2,3] More recently, alternative
workup and purification strategies have been developed
based on affinity separation.[4] In the latter approaches,
chemical reactions are performed in solution phase so that
the process can be monitored by standard analytical tools.
After completion, an additional medium, immiscible with
the reaction mixture, is added. The additional phase is
either a solvent or a solid that has a distinct affinity for the
tagged compound, but no affinity whatsoever for the other
reagents and products. This way, affinity binding will lead
[a] Institute for Molecules and Materials, Radboud University
Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax: +31-24-365-3202
E-mail: F.Rutjes@science.ru.nl
[b] Eindhoven University of Technology,
P. O. Box 513, 5600 MB Eindhoven, The Netherlands
[c] Organon N. V.,
P. O. Box 20, 5340 BH Oss, The Netherlands
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F. P. J. T. Rutjes et al.
FULL PAPER
Scheme 1. Synthesis of UPy-tagged U-4CR precursor 5.
Table 1. U-4CRs and comparison of purification methods.
Figure 1. Schematic representation of purification by hydrogen
bonding.
drogen bonds are broken and the tagged compound dissoci-
ates from the resin and dissolves again. Subsequent fil-
tration of the polymer beads and evaporation of the solvent
leads again to the tagged compound in pure form, which
can be subjected to a next reaction. Because this method in
principle combines the advantages of solution-phase syn-
thesis and solid-phase purification, and therefore might be
potentially useful for automated synthesis, we set out to re-
alize a proof of this concept.
Entry Substrate
R
R1
R2
Yield [%] Yield [%]
CC[a]
AS[b]
1
2
3
4
5
6
7
8
9
10
HCϵCCH2
HCϵCCH2
nBu
nBu
tBu
cHex
tBu
tBu
cHex
77
82
84
76
75
83
87
89
84
84
HCϵCCH2 3-butenyl
PMB[c]
PMB[c]
3-butenyl
3-butenyl
[a] CC = column chromatography. [b] AS = affinity separation. [c]
PMB = p-methoxybenzyl.
plied, which was previously optimized for catalyst recycl-
ing.[20] The presence of methanol in the reaction mixture
Results and Discussion
Initially, we chose to equip a benzoate with the UPy AT, forced us to evaporate the solvent after completion of the
which yielded a compound that could be used in Ugi 4- reaction, and redissolve the crude product in chloroform
component reactions (U-4CRs).[23] This versatile multi- before affinity binding. The purity of the products appeared
component reaction (MCR) has been studied extensively, to be similar, albeit that in some cases the compounds that
and applications in organic synthesis include the formation were purified through AS appeared to be slightly yellow,
of peptides,[24] glycopeptides,[25] β-lactams,[26] iminohydan- while the products purified by column chromatography
toins[27] and various other biologically active compound were always colorless. Simple treatment of the products ob-
classes.
tained by affinity separation with activated charcoal was
The isocytosine 2, obtained by two high-yielding steps,[28] sufficient to yield colorless compounds as well. These re-
was treated with carbonyl diimidazole[29] and subsequently sults demonstrate that our assumption on the applicability
with the benzylamine derivative 3 in a one-pot procedure of the UPy tags in organic synthesis was justified, and indi-
to give compound 4 in modest yield (Scheme 1). Saponifica- cate that this methodology may be more widely applicable
tion of the methyl ester gave the desired UPy-tagged ben- to purify products obtained by other organic reactions.
zoic acid 5 in excellent yield. Compound 5 was subjected to
To further expand the value of this purification protocol,
standard U-4CR conditions using readily available reagents it was decided to investigate whether substrate molecules
(Table 1). Due to the rather poor solubility of UPy-tagged could be equipped with a cleavable linker bearing the UPy
compound 5 in methanol, a 1:1 mixture of methanol/chlo- AT. This would offer the possibility of isolating the pure
roform was used as the solvent. All reactions proceeded product after the linker is removed in the final synthesis
smoothly, which showed the compatibility of U-4CRs with step by an additional AS cycle (Figure 2).
the UPy AT. Clearly, the tolerance of the UPy tag towards
chemical transformations is a strict requirement for our no longer affinity for the UPy-equipped resin. Addition of
purposes. the resin will therefore abstract only the linker that still be-
After the product is freed from the tagged linker, it has
As can be read from Table 1, products 6 to 10 were iso- ars the UPy functionality from solution, so filtration and
lated in good yields using standard column chromatog- subsequent solvent evaporation should yield the substrate
raphy. Isolation of the same products using the hydrogen- in pure form. We decided to use p-hydroxybenzyl alcohol
bonding properties of the tag (affinity separation) as de- as the starting compound for the synthesis of linker 15
scribed above, provided the same products in slightly higher (Scheme 2). This alkoxybenzyl alcohol based linker offers a
yields. In all cases, the ArgoPore resin-bound tag 1 was ap- handle to couple substrates with, and can be cleaved under
4198
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A Novel Purification Method in Organic Synthesis Using Hydrogen Bonding
FULL PAPER
scribed.[31] Thus, treatment of the AT-equipped substrate 20
with an excess of a nucleophilic amine and triethylamine as
a base at room temperature, gave indeed substitution prod-
ucts 21–23 after 24 h (Table 2). A large excess of amine was
used to force the reactions to go to completion, which is a
necessity for successful application of our new purification
protocol. All compounds functionalized with the UPy-
based AT will be bound by the tagged resin, so that dis-
crimination between starting material and product is not
possible. According to TLC, full conversion was obtained
in all cases and the products were again purified both by
column chromatography and affinity separation.
Figure 2. Release and separation of substrate molecules from the
AT.
mild, acidic conditions.[30] Hence, this moiety enables facile
acid-mediated cleavage of substrates from the tag after puri-
fication by our method.
Scheme 2. Synthesis of cleavable linker 15.
Alkylation of p-hydroxybenzyl alcohol 11 with bromide
12 under basic conditions went smoothly to give adduct 13
in excellent yield. After saponification of the methyl ester,
and subsequent protection of the benzylic hydroxy group,
compound 15 was obtained without difficulties.
The benzoic acid 15 was treated with DPPA to give the
corresponding acyl azide, which was transformed into the
intermediate isocyanate 16 at elevated temperatures. After
Scheme 3. Completion of acid-labile linker 17.
addition of (2-ethylpentyl)isocytosine and
a
catalytic
The results are shown in Table 2. In case column
amount of DMAP, the mixture was heated again to give chromatography was applied, an extraction was performed
tagged linkers 17 in reasonable yield. The same procedure prior to the purification, while during affinity separation,
was also carried out using adamantyl-substituted isocytos- the crude mixture was directly subjected to the resin with-
ine, but this resulted in virtually insoluble adducts, which out any workup. Again, the yields of the products that were
could not be fully characterized by common spectroscopic purified by column chromatography were lower than the
methods. Next, the deprotection of the benzylic alcohol and yields encountered with affinity separation, but the purity
coupling of this linker with a simple substrate was pursued of the compounds isolated was comparable according to
(Scheme 3). Deacetylation was performed under standard NMR spectroscopy. The next step, cleavage of the tagged
conditions to give the alcohol 18 in excellent yield. It was linker and purification of the products using the tagged
decided to couple the linkers with benzoic acid derivative resin, was carried out with compounds 21 to 23 which were
19, since the resulting compound 20 was anticipated to eas- obtained after affinity separation. A 95:5 mixture of tri-
ily undergo nucleophilic aromatic substitutions with amines fluoroacetic acid/water was used to cleave the Wang-type
to give the aniline derivatives. Coupling of 19 with linkers linker and products 24–26 were formed as anticipated. The
18 was performed using EDC and DMAP in chloroform to cleaved linker was separated by affinity separation and
provide compound 20 in a yield of 87%. Next, 20 was sub- products 24–26 were isolated in excellent yield (Table 2).[32]
jected to aromatic substitution reactions, which are well de- The purity of isolated compounds 24 and 25 was compar-
Eur. J. Org. Chem. 2007, 4197–4204
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F. P. J. T. Rutjes et al.
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Table 2. Aromatic substitution, followed by purification.
Entry
R
Compound
Yield (CC)[a]
Yield (AS)
Product
Yield (AS)
1
2
3
H2C=CHCH2
HCϵCCH2
p-MeOC6H4CH2
21
22
23
75%
73%
Ͼ95%
Ͼ95%
Ͼ95%
Ͼ95%
24
25
26
Ͼ95%
Ͼ95%
86%[b]
[a] Prior to CC an extraction was carried out. [b] To obtain a pure sample, treatment with activated charcoal was required.
using ACROS silica gel (0.035–0.070 mm and ca. 6 nm pore dia-
meter). Mass spectra and accurate mass measurements were carried
out using a Fisons (VG) Micromass 7070E or a Finnigan
MAT900S instrument. Solvents were distilled from appropriate
drying agents prior to use. Unless otherwise noted, all chemicals
were purchased and used as such..
able to the products isolated by column chromatography,
but treatment of 26 with activated charcoals was required
to obtain the product in pure form. Nevertheless, this ap-
proach offers the possibility of carrying out multiple solu-
tion-phase steps with a straightforward purification by the
hydrogen-bonding protocol to yield the products in excel-
lent purity.
4-{3-[6-(1-Ethylpentyl)-4-oxo-1,4-dihydropyrimidin-2-yl]ureido-
methyl}benzoic Acid (5): To a stirred solution of the (ethylpentyl)-
isocytosine 2 (3.00 g, 14.3 mmol) in DMF (75 mL) were added
Et3N (6.1 mL, 35 mmol), carbonyl diimidazole (2.55 g, 15.7 mmol)
and a catalytic amount of DMAP. The mixture was stirred at room
temp. for 2 h, then amine 3 (HCl salt, 5.86 g, 29.0 mmol) and Et3N
(5.2 mL, 30 mmol) were added. The mixture was stirred at room
temp. for an additional 20 h, and the solvent was removed under
reduced pressure. The residue was taken up in H2O/CH2Cl2 (1:1
v/v, 250 mL), and the layers were separated. The aqueous phase
was back-extracted with CH2Cl2 (2ϫ100 mL), and the combined
organic layers were washed with aqueous NH4Cl (150 mL), dried
(MgSO4), and concentrated to give a light yellow solid. Precipi-
tation in Et2O gave compound 4 (3.64, 64%) as a white solid. FTIR
Conclusions
We have successfully developed a new workup and purifi-
cation method based on quadruple hydrogen-bonding inter-
actions. Products of Ugi multicomponent reactions were se-
lectively bound by a tagged resin, and were isolated in high
yield and purity. Installation of a cleavable linker offered
the possibility of isolating products after linker removal
using the same affinity protocol, as was successfully demon-
strated in nucleophilic aromatic substitution reactions.
(ATR): ν = 2951, 2931, 2853, 1720, 1693, 1650, 1572, 1522, 1276,
˜
1253, 1105, 848, 786 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 13.07
(s, 1 H), 12.11 (s, 1 H), 10.96 (t, J = 5.6 Hz, 1 H), 8.00 (d, J =
8.1 Hz, 2 H), 7.44 (d, J = 8.1 Hz, 2 H), 5.81 (s, 1 H), 4.51 (d, J =
5.8 Hz, 2 H), 3.89 (s, 3 H), 2.31–2.27 (m, 1 H), 1.69–1.49 (m, 4 H),
1.33–1.18 (m, 4 H), 0.89 (t, J = 7.4 Hz, 3 H), 0.52 (t, J = 7.4 Hz,
3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 172.7, 166.5, 156.6,
155.3, 154.3, 143.7, 129.6 (2 C), 128.7, 127.0 (2 C), 106.1, 52.0,
45.4, 43.2, 32.9, 29.4, 26.7, 22.6, 14.0, 11.9 ppm. Without further
purification, compound 4 (400 mg, 1.00 mmol) was dissolved in
aqueous NaOH (2 )/THF (1:1 v/v, 10 mL). The mixture was
heated to 50 °C overnight, and then concentrated in vacuo. The
resulting solution was then carefully acidified using concentrated
HCl, upon which a white solid precipitated from the solution. The
white solid was filtered off, washed with water and dried in vacuo
to give the desired acid 5 (379 mg, 97%) in pure form. M.p. 164 °C.
Experimental Section
General: All reactions were carried out under dry argon. Standard
syringe techniques were applied to the transfer of dry solvents and
air- or moisture-sensitive reagents. Rf values were obtained using
thin layer chromatography (TLC) on silica gel coated plates (Merck
60 F254) with the indicated solvent mixture, and compounds were
detected with UV light or with aqueous potassium permanganate.
Melting points were determined with a Büchi melting point appara-
tus B-545. IR spectra were recorded with an ATI Mattson Genesis
Series FTIR spectrometer, equipped with a Harrick Split Pea ATR
apparatus. Absorptions are reported in cm–1. NMR spectra were
recorded with a Bruker DMX 300 (300 MHz), and a Varian 400
(400 MHz) spectrometer in CDCl3 solutions (unless otherwise re-
ported) using tetramethylsilane (TMS) as internal standard; chemi-
cal shifts are given in ppm. Coupling constants are reported as J
values in Hz. Column or flash chromatography was carried out
FTIR (ATR): ν = 2955, 2928, 2861, 1691, 1650, 1575, 1523, 1422,
˜
1258, 850, 738 cm–1. 1H NMR ([D6]DMSO, 400 MHz): δ = 8.26
(br. s, 1 H), 7.91 (d, J = 8.3 Hz, 2 H), 7.42 (d, J = 8.3 Hz, 2 H),
5.75 (s, 1 H), 4.45 (d, J = 5.8 Hz, 2 H), 2.24–2.17 (m, 1 H), 1.47–
4200
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A Novel Purification Method in Organic Synthesis Using Hydrogen Bonding
FULL PAPER
1.36 (m, 4 H), 1.25–1.02 (m, 4 H), 0.79 (t, J = 7.1 Hz, 3 H), 0.72
(t, J = 7.4 Hz, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
170.2, 167.0, 161.6, 154.7, 151.7, 144.0, 129.5, 129.4 (2 C), 127.1 (2
gylamine (14 mg, 0.25 mmol), 4-pentenal (21 mg, 0.25 mmol) and
tert-butyl isocyanide (21 mg, 0.25 mmol) was treated as described
above, to give 51 mg (84% yield) of the desired compound as a
C), 104.9, 47.6, 42.5, 32.9, 29.0, 26.4, 22.1, 13.8, 11.7 ppm. HRMS colorless oil by column chromatography, and 54 mg (89%) as a
(ESI): calcd. for C20H27N4O4 [M + H]+ 387.2032, found 387.2025.
light yellow oil by resin purification. FTIR (ATR): ν = 3300, 3218,
˜
2958, 2924, 2868, 1692, 1640, 1575, 1524, 1446, 1416, 1364, 1308,
General Procedure for the Purification of Compounds 6–10 by Affin-
ity Separation: To a solution of 1 equiv. of compounds 6–10 in
chloroform (2 mL) were added 10 equiv. of Et3N and 10 equiv. of
the amine. The mixture was stirred for 24 h. The tagged resin
(10 equiv. of binding sites relative to the amount of 6–10) was
added to the crude mixture, and the flask was put in a shaking
apparatus for 16 h. The solvent was filtered off, and the resin was
washed with CHCl3. After transferring the resin to a flask, a 2:1
mixture of DMF/MeOH (10 mL) was added, and the mixture was
shaken for 3 h. The solvent was filtered off and evaporated to give
the desired compound with high purity and yield as indicated in
Table 1.
1
1247, 1143, 1022, 910, 849, 806, 728, 646 cm–1. H NMR (CDCl3,
400 MHz): δ = 13.08 (s, 1 H), 12.10 (s, 1 H), 10.92 (s, 1 H), 7.55
(br. s, 2 H), 7.45 (d, J = 8.0 Hz, 2 H), 6.42 (br. s, 1 H), 5.86–5.08
(m, 2 H), 5.06–4.98 (m, 2 H), 4.79 (m, 1 H), 4.49 (d, J = 5.8 Hz, 2
H), 4.17–4.12 (m, 1 H), 3.97–3.93 (m, 1 H), 2.30–2.26 (m, 2 H),
2.16–2.11 (m, 4 H), 1.68–1.48 (m, 4 H), 1.32 (s, 9 H), 1.30–1.22 (m,
4 H), 0.89–0.83 (m, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
172.7, 169.0, 156.6, 155.3, 154.4, 141.3, 137.1, 133.6, 127.3 (2 C),
127.2 (2 C), 115.4, 106.1, 80.1, 72.9, 65.8, 58.4, 51.3, 45.4, 43.2,
37.2, 33.0, 30.7, 29.4, 28.8 (3 C), 27.6, 26.8, 22.6, 14.1, 11.9 ppm.
HRMS (ESI): calcd. for C33H46N6O4Na [M + Na]+ 613.3478,
found 613.3445.
N-[1-(tert-Butylcarbamoyl)pentyl]-4-{3-[6-(1-ethylpentyl)-4-oxo-1,4-
dihydropyrimidin-2-yl]ureidomethyl}-N-(prop-2-ynyl)benzamide (6):
A mixture of propargylamine (14 mg, 0.25 mmol), tert-butyl isocy-
anide (21 mg, 0.25 mmol), pentanal (22 mg, 0.25 mmol) and acid 5
(39 mg, 0.10 mmol) in MeOH/CHCl3 (1:1 v/v, 2 mL) was stirred
for 3 d. The solvent was evaporated, and the residue was purified
by column chromatography (1Ǟ3% MeOH in CHCl3) to give the
desired adduct in 77% yield as a colorless oil, or purified with the
N-[1-(tert-Butylamino)-1-oxohex-5-en-2-yl]-4-({3-[6-(hept-3-yl)-4-
oxo-1,4-dihydropyrimidin-2-yl]ureido}methyl)-N-(4-methoxybenzyl)-
benzamide (9): A mixture of 39 mg (0.10 mmol) of compound 5,
34 mg (0.25 mmol) of 4-methoxybenzylamine, 21 mg (0.25 mmol)
of 4-pentenal, and 21 mg (0.25 mmol) of tert-butyl isocyanide was
treated as described above, to give 51 mg (76% yield) of the desired
compound as a colorless oil by column chromatography, and 54 mg
(84%) as a light yellow oil by resin purification. FTIR (ATR): ν =
˜
tagged resin (83% yield). FTIR (ATR): ν = 3309, 3218, 2954, 2924,
˜
3218, 3023, 2958, 2924, 2868, 1692, 1645, 1580, 1519, 1450, 1256,
2872, 1697, 1949, 1580, 1519, 1450, 1411, 1308, 1251, 845, 728,
1
1148, 1053, 910, 845, 728 cm–1. H NMR (400 MHz, CDCl3): δ =
1
603 cm–1. H NMR (CDCl3, 400 MHz): δ = 13.09 (s, 1 H), 12.11
13.07 (s, 1 H), 12.07 (s, 1 H), 10.90 (s, 1 H), 7.37 (br. s, 4 H), 7.18–
7.14 (m, 1 H), 6.75–6.60 (m, 4 H), 5.78 (s, 1 H), 5.77–5.70 (m, 1
H), 5.00–4.93 (m, 2 H), 4.62–4.56 (m, 3 H), 4.46–4.44 (m, 2 H),
3.74 (s, 3 H), 2.31–2.24 (m, 1 H), 2.14–1.83 (m, 4 H), 1.69–1.48 (m,
4 H), 1.33–1.13 (m, 13 H), 0.87 (t, J = 7.5 Hz, 3 H), 0.85 (t, J =
7.3 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.5, 173.0,
169.3, 159.7, 156.8, 155.6, 154.6, 140.8, 137.3, 134.9, 129.6 (2 C),
127.6 (2 C), 126.9 (2 C), 119.6, 115.6 (2 C), 113.1, 112.8, 106.2,
60.2, 55.1, 51.7, 51.0, 45.3, 43.0, 32.8, 30.5, 29.2, 28.5 (3 C), 26.5,
22.4, 13.8, 11.6 ppm. HRMS (ESI): calcd. for C38H52N6O5Na [M
+ Na]+ 695.3897, found 695.3839.
(s, 1 H), 10.93 (t, J = 4.8 Hz, 1 H), 7.61–7.51 (br. s, 2 H), 7.45 (d,
J = 8.0 Hz, 2 H), 6.51–6.37 (br. s, 1 H), 5.81 (s, 1 H), 4.80–4.70
(br. s, 1 H), 4.50 (d, J = 5.8 Hz, 2 H), 4.23–4.08 (m, 1 H), 4.02–
3.89 (m, 1 H), 2.33–2.24 (m, 1 H), 2.27 (t, J = 2.4 Hz, 1 H), 2.07–
1.93 (m, 2 H), 1.72–1.47 (m, 6 H), 1.38–1.17 (m, 6 H), 1.33 (s, 9
H), 0.90–0.84 (m, 9 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
173.1, 169.6, 162.6, 156.8, 155.6, 154.6, 141.4, 133.9 (2 C), 127.5 (2
C), 106.2, 80.1, 72.7, 59.1, 51.1, 45.3, 43.1, 37.0, 36.4, 32.8, 29.2,
28.6, 28.5, 27.9, 26.5, 22.4, 13.9, 13.8, 11.6 ppm. HRMS (ESI):
calcd. for C33H48N6O4Na [M + Na]+ 615.3635, found 615.3599.
N-[1-(Cyclohexylcarbamoyl)pentyl]-4-{3-[6-(1-ethylpentyl)-4-oxo-
1,4-dihydropyrimidin-2-yl]ureidomethyl}-N-(prop-2-ynyl)benzamide
(7): A mixture of acid 5 (39 mg, 0.10 mmol), propargylamine
(14 mg, 0.25 mmol), cyclohexyl isocyanide (27 mg, 0.25 mmol), and
pentanal (22 mg, 0.25 mmol) was treated as described above to give
51 mg (82% yield) of the desired adduct as a colorless oil by col-
umn chromatography, and 54 mg (87%) as a light yellow oil by
N-[1-(Cyclohexylamino)-1-oxohex-5-en-2-yl]-4-({3-[6-(hept-3-yl)-4-
oxo-1,4-dihydropyrimidin-2-yl]ureido}methyl)-N-(4-methoxybenzyl)-
benzamide (10): A mixture of compound 5 (39 mg, 0.10 mmol), 4-
methoxybenzylamine (34 mg, 0.25 mmol), 4-pentenal (21 mg,
0.25 mmol) and cyclohexyl isocyanide (27 mg, 0.25 mmol) was
treated as described above, to give 51 mg (75% yield) of the desired
compound as a colorless oil by column chromatography, and 54 mg
resin purification. FTIR (ATR): ν = 3304, 3228, 3023, 2954, 2929,
˜
(84%) as a light yellow oil by resin purification. FTIR (ATR): ν =
˜
2855, 1695, 1655, 1640, 1583, 1527, 1446, 1411, 1305, 1254, 851,
806, 731, 668, 649 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 13.08
(s, 1 H), 12.10 (s, 1 H), 10.92 (s, 1 H), 7.61–7.51 (m, 2 H), 7.43 (d,
J = 7.9 Hz, 2 H), 6.54 (br. s, 1 H), 5.81 (s, 1 H), 4.79 (m, 1 H),
4.50 (d, J = 5.7 Hz, 2 H), 4.20–4.09 (m, 1 H), 3.99–3.88 (m, 1 H),
3.79–3.70 (m, 1 H), 2.33–2.26 (m, 1 H), 2.29 (t, J = 2.4 Hz, 1 H),
2.07–1.99 (m, 2 H), 1.90–1.80 (m, 2 H), 1.71–1.50 (m, 8 H), 1.38–
1.15 (m, 12 H), 0.90–0.84 (m, 9 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 173.1, 169.5, 156.9, 155.7, 154.7, 141.5, 133.9, 127.5
(2 C), 127.4 (2 C), 106.3, 80.1, 72.7, 58.7, 47.9, 45.3, 43.1, 37.2,
32.8, 32.7, 29.7, 29.3, 28.5, 28.0, 26.6, 25.5, 24.6, 22.4, 13.9, 13.8,
11.7 ppm. HRMS (ESI): calcd. for C35H50N6O4Na [M + Na]+
641.3791, found 641.3742.
3309, 3049, 2924, 2855, 1653, 1584, 1528, 1446, 1333, 1251, 1148,
1
1048, 910, 728, 690 cm–1. H NMR (400 MHz, CDCl3): δ = 13.06
(s, 1 H), 12.06 (s, 1 H), 10.88 (s, 1 H), 7.36 (br. s, 4 H), 7.23–7.14
(m, 1 H), 6.84–6.59 (m, 4 H), 5.77 (s, 1 H), 5.75–5.70 (m, 1 H),
5.02–4.90 (m, 2 H), 4.58–4.49 (m, 3 H), 4.45–4.32 (m, 2 H), 3.73
(s, 3 H), 3.62–3.58 (m, 1 H), 2.31–2.23 (m, 1 H), 2.15–1.49 (m, 12
H), 1.32–1.00 (m, 10 H), 0.86 (t, J = 7.5 Hz, 3 H), 0.84 (t, J =
7.3 Hz, 3 H) ppm. HRMS (ESI): calcd. for C40H55N6O5Na [M +
H]+ 699.4233, found 699.4169.
Methyl 4-{[4-(Hydroxymethyl)phenoxy]methyl}benzoate (13): To a
solution of p-hydroxybenzyl alcohol (5.00 g, 40.3 mmol) in acetone
(150 mL) were added methyl 4-(bromomethyl)benzoate (8.30 g,
36.3 mmol) and K2CO3 (5.60 g, 40.3 mmol). The mixture was re-
fluxed overnight, cooled to room temp. and concentrated in vacuo.
The residue was taken up in a 1:1 mixture of aqueous NaOH
N-[1-(tert-Butylcarbamoyl)pent-4-enyl]-4-{3-[6-(1-ethylpentyl)-4-
oxo-1,4-dihydropyrimidin-2-yl]ureidomethyl}-N-(prop-2-ynyl)benz-
amide (8): A mixture of compound 5 (39 mg, 0.10 mmol), propar-
Eur. J. Org. Chem. 2007, 4197–4204
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4201

F. P. J. T. Rutjes et al.
FULL PAPER
(0.625 )/EtOAc (300 mL), and the layers were separated. The
aqueous phase was back-extracted with EtOAc (2ϫ100 mL), and
the combined organic layers were washed with water, dried
(MgSO4) and the solvents evaporated. The residue was precipitated
in aqueous NaOH (0.625 ) to give the desired product (9.70 g,
1.33–1.25 (m, 4 H), 0.94–0.84 (m, 6 H) ppm. HRMS (ESI): calcd.
for C28H35N4O5 [M + H+] 507.2607, found 507.2653.
1-[6-(1-Ethylpentyl)-4-oxo-1,4-dihydropyrimidin-2-yl]-3-(4-{[(4-(hy-
droxymethyl)phenoxy]methyl}phenyl)urea (18): To a suspension of
17 (0.795 g, 1.57 mmol) in methanol (20 mL) was added K2CO3
(1.08 g, 7.85 mmol). The mixture was stirred at room temp. for 5 h,
and brought to neutral pH using aqueous NH4Cl. The methanol
was evaporated, and the residue was precipated in water (25 mL).
After filtration, the crude product was washed with Et2O (15 mL)
and dried to give 18 as a white solid (0.693 g, 95%). FTIR (ATR):
98%) as a white solid. M.p. 115–116 °C. FTIR (ATR): ν = 3304,
˜
2958, 2915, 2959, 1714, 1282 cm–1. 1H NMR (CDCl3, 400 MHz):
δ = 8.04 (d, J = 7.8 Hz, 2 H), 7.50 (d, J = 8.0 Hz, 2 H), 7.29 (d, J
= 8.2 Hz, 2 H), 6.95 (d, J = 8.0 Hz, 2 H), 5.13 (s, 2 H), 4.62 (s, 2
H), 3.92 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 166.1,
157.7, 141.9, 133.5, 129.7 (2 C), 128.4 (2 C), 126.7 (2 C), 114.7 (2
C), 69.4, 65.0, 52.2 ppm. HRMS (EI) calcd. for C16H16O4 [M+]
272.1049, found 272.1049.
ν = 2956, 2925, 2862, 1640, 1605, 1508, 1445, 1406, 1227, 1009,
˜
1
818 cm–1. H NMR (CDCl3/CD3OD, 400 MHz): δ = 7.65 (br. s, 1
H), 7.46 (br. s, 2 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.6 Hz,
2 H), 6.96 (d, J = 8.3 Hz, 2 H), 5.94 (s, 1 H), 5.06 (s, 2 H), 4.57 (s,
2 H), 2.44–2.35 (m, 1 H), 1.69–1.58 (m, 4 H), 1.36–1.22 (m, 4 H),
0.96–0.85 (m, 6 H) ppm. HRMS (ESI): calcd. for C26H32N4O4Na
[M + Na+] 487.2321, found 487.2321.
4-{[4-(Hydroxymethyl)phenoxy]methyl}benzoic Acid (14): A suspen-
sion of 13 (6.45 g, 23.7 mmol) in aqueous NaOH (2.0 , 150 mL)
was stirred at 50 °C for 12 h. After cooling the mixture to room
temp., it was acidified with aqueous HCl (5.0 , 75 mL) and the
solid was filtered off. After washing (0.01  HCl, 50 mL) and dry-
ing in vacuo, compound 14 (6.12 g, Ͼ99%) was obtained as a white
4-(4-{3-[6-(1-Ethylpentyl)-4-oxo-1,4-dihydropyrimidin-2-yl]ureido}-
benzyloxy)benzyl 4-Fluoro-3-nitrobenzoate (20): To a solution of 18
(0.204 g, 0.439 mmol) and Et3N in (0.60 mL, 4.40 mmol) in CHCl3
(25 mL) were added 4-fluoro-3-nitrobenzoic acid (19, 0.814 g,
4.40 mmol), N-ethyl-NЈ-(3-dimethylaminopropyl)carbodiimide hy-
drochloride (EDC) (0.555 g, 4.40 mmol) and a catalytic amount of
DMAP. The mixture was refluxed for 24 h, and cooled to room
temp. The solvent was evaporated, and the residue was precipitated
in methanol (15 mL). After filtration, washing with methanol
(10 mL) and drying, 20 (0.241 g, 87%) was isolated as a yellow
solid. M.p. 197–198 °C. FTIR (ATR): ν = 3396, 2930, 2803, 1690,
˜
1236 cm–1 1H NMR ([D6]DMSO, 400 MHz): δ = 7.95 (d, J =
.
8.2 Hz, 2 H), 7.53 (d, J = 8.2 Hz, 2 H), 7.23 (d, J = 8.8 Hz, 2 H),
6.96(d,J=8.8 Hz,2H),5.17(s,2H),4.41(s,2H)ppm.13CNMR([D6]-
DMSO, 75 MHz): δ = 167.0, 156.8, 141.8, 134.8, 129.3 (2 C), 127.8
(2 C), 127.1 (2 C), 114.4 (2 C), 68.7, 62.6 ppm. HRMS (EI): calcd.
for C15H14O4 [M+] 258.0892, found 258.0893.
4-{[4-(Acetoxymethyl)phenoxy]methyl}benzoic Acid (15): A solution
of 14 (4.00 g, 15.5 mmol) and Et3N (10.8 mL, 77.4 mmol) in
CH2Cl2 (100 mL) was cooled to 0 °C, and Ac2O (4.40 mL,
46.5 mmol) was added dropwise. The mixture was warmed to room
temp. and stirred for 5 h. After diluting the mixture with aqueous
HCl (1.0 , 100 mL), the layers were separated, and the aqueous
phase was back-extracted with CHCl3 (2ϫ100 mL). The combined
organic layers were washed with water (250 mL), and the solvents
evaporated. The residue was precipitated from water (100 mL) to
solid. FTIR (ATR): ν = 3023, 2952, 2924, 2868, 1719, 1694, 1649,
˜
1606, 1571, 1539, 1508, 1321, 1278, 1222, 1176, 1112, 1011, 909,
1
824 cm–1. H NMR (CDCl3, 400 MHz): δ = 13.11 (s, 1 H), 12.32
(s, 1 H), 12.29 (s, 1 H), 8.73 (dd, J = 7.2, 2.2 Hz, 1 H), 8.32 (ddd,
J = 8.7, 4.2, 2.2 Hz, 1 H), 7.71 (d, J = 8.6 Hz, 2 H), 7.40 (d, J =
8.7 Hz, 2 H), 7.37 (d, J = 8.7 Hz, 2 H), 7.34 (d, J = 8.9 Hz, 1 H),
6.98 (d, J = 8.7 Hz, 2 H), 5.94 (d, J = 1.5 Hz, 1 H), 5.32 (s, 2 H),
5.07 (s, 2 H), 2.39–2.31 (m, 1 H), 1.75–1.55 (m, 4 H), 1.36–1.19 (m,
4 H), 0.92 (t, J = 7.6 Hz, 3 H), 0.88 (t, J = 7.6 Hz, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 172.64, 163.16, 159.49, 158.79,
155.91, 155.49, 154.44, 137.64, 136.41, 136.28, 132.03, 130.23,
127.98, 127.66, 127.14, 120.70, 118.66, 188.38, 114.97, 106.45,
69.78, 67.65, 45.56, 33.08, 29.50, 26.84, 22.68, 14.11, 11.94 ppm.
HRMS (FAB): calcd. for C33H35FN5O7 [M + H+] 632.2521, found
632.2495.
1
give 15 (4.59 g, 99%) as a white solid. H NMR (400 MHz, [D6]-
DMSO): δ = 12.90 (br. s, 1 H), 7.92 (d, J = 8.0 Hz, 2 H), 7.52 (d,
J = 8.0 Hz, 2 H), 7.27 (d, J = 8.4 Hz, 2 H), 6.98 (d, J = 8.4 Hz, 2
H), 5.17 (s, 2 H), 4.95 (s, 2 H), 1.99 (s, 3 H) ppm. 13C NMR ([D6]-
DMSO, 75 MHz): δ = 170.5, 161.7, 158.1, 142.8, 130.3 (2 C), 130.0
(2 C), 128.6, 128.5, 126.8 (2 C), 114.8 (2 C), 69.3, 66.1, 21.3 ppm.
HRMS (EI): calcd. for C17H16O5 [M+] 300.0998, found 300.0999.
General Procedure for Nucleophilic Aromatic Substitution on Com-
pounds 20 and Subsequent Purification Using the Tagged Resin: To a
solution of compound 20 (20 mg, 32 µmol, 1 equiv.) in chloroform
(2 mL) were added 10 equiv. of Et3N and 10 equiv. of the amine.
The mixture was stirred for 24 h. The tagged resin (10 equiv. of
binding sites relative to the amount of 20) was added to the crude
mixture, and the flask was put in a shaking apparatus for 16 h. The
resin was filtered off and washed with CHCl3. After transferring
the resin to a flask, a 2:1 mixture of DMF/MeOH (10 mL) was
added, and the mixture was shaken for 3 h. The solvent was filtered
off and evaporated to give the desired compound with high purity
and yield as indicated in Table 2. The compounds were then di-
rectly subjected to the cleavage conditions as described for com-
pound 24.
1-({[4-(4-(Acetoxymethyl)phenoxy]methyl}phenyl)-3-[6-(1-ethyl-
pentyl)-4-oxo-1,4-dihydropyrimidin-2-yl]urea (17): To a solution of
15 (2.00 g, 6.66 mmol) and Et3N (1.90 mL, 13.3 mmol) in CHCl3
(150 mL), (PhO)2P(O)N3 (1.70 mL, 8.00 mmol) was added drop-
wise. The mixture was stirred at room temp. for 6 h, then refluxed
for 12 h. After cooling the solution to room temp., the (ethylpentyl)-
isocytosine 2 (3.01 g, 14.4 mmol) and a catalytic amount of DMAP
were added, and the mixture was refluxed for another 5 h. After
cooling the mixture to room temp., the solution was concentrated
in vacuo. The residue was taken up in CHCl3/H2O (1:1 v/v,
200 mL). The layers were separated, and the aqueous phase was
back-extracted with CHCl3 (2ϫ100 mL). The combined organic
layers were washed with water, dried and the solvents evaporated.
The residue was precipitated in MeOH and dried to give 17 (2.16 g,
64%) as a white solid. FTIR (ATR): ν = 3022, 2956, 2925, 2866,
4-(Allylamino)-3-nitrobenzoic Acid (24): Reaction of 20 according
to the general procedure with allylamine provided 21. M.p. dec.
˜
1737, 1648, 1605, 1581, 1508, 1321, 1219, 1173, 1017, 822 cm–1. 1H
NMR (CDCl3, 400 MHz): δ = 13.11 (s, 1 H), 12.27 (s, 1 H), 12.25 Ͼ200 °C. FTIR (ATR): ν = 3373, 2924, 1697, 1619, 1506, 1256,
˜
(s, 1 H), 7.71 (d, J = 8.3 Hz, 2 H), 7.37 (d, J = 8.5 Hz, 2 H), 7.25
(d, J = 8.6 Hz, 2 H), 6.91 (d, J = 8.6 Hz, 2 H), 5.92 (s, 1 H), 5.01
(br. s, 4 H), 2.36–2.31 (m, 1 H), 2.05 (s, 3 H), 1.68–1.55 (m, 4 H),
1217, 1096, 1014, 798, 759 cm–1. 1H NMR (CDCl3, 400 MHz): δ =
13.12 (s, 1 H), 12.31 (s, 1 H), 12.25 (s, 1 H) 8.89 (dd, J = 4.4,
2.0 Hz, 1 H), 8.47 (br. t, J = 5.3 Hz, 1 H), 8.07–8.03 (m, 1 H), 7.71
4202
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4197–4204

A Novel Purification Method in Organic Synthesis Using Hydrogen Bonding
FULL PAPER
(d, J = 8.5 Hz, 2 H), 7.41–7.30 (m, 3 H), 6.96 (dd, J = 8.8, 2.2 Hz, 130.11, 129.93, 129.28, 128.24, 128.02, 120.70, 119.02, 117.72,
2 H), 6.83 (d, J = 9.1 Hz, 2 H), 5.98–5.89 (m, 2 H), 5.33–5.27 (m, 114.84, 113.78, 112.99, 112.68, 106.47, 69.82, 66.63, 55.33, 47.30,
4 H), 5.01 (s, 2 H), 4.04–4.01 (m, 2 H), 2.39–2.32 (m, 1 H), 1.73– 45.57, 33.09, 29.51, 26.85, 22.69, 14.12, 11.95 ppm. HRMS (FAB):
1.57 (m, 4 H), 1.35–1.24 (m, 4 H), 0.92 (t, J = 7.3 Hz, 3 H), 0.88
calcd. for C41H45N6O8 [M + H]+ 749.3299, found 749.3309. Treat-
ment of compound 23 without further purification with TFA/H2O
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 173.1,
165.0, 158.9, 155.8, 154.8, 147.6, 136.4, 132.3, 131.5, 130.1 (2 C), as described above, gave acid 26 in quantitative yield. A pure sam-
129.5, 128.9, 128.6, 128.4, 128.2 (2 C), 120.9, 120.7, 117.7 (2 C), ple of 26 was obtained after filtration through a short silica plug
115.0 (2 C), 113.8, 106.6, 77.2, 69.8, 69.7, 66.6, 45.4, 32.9, 29.7, (86% yield). FTIR (ATR): ν = 3360, 2950, 2920, 2850, 1718, 1619,
˜
29.3, 26.7, 22.5, 13.9, 11.7 ppm. Without further purification com-
pound 21 (9.8 mg, 14.6 µmol) was dissolved in TFA/H2O (95:5
v/v, 2 mL) and the mixture stirred for 90 min. The solvent was
evaporated, and the residue was taken up in 20 mL of CHCl3. To
the resulting solution 0.50 g of the tagged resin was added
(0.14 mmol AT groups), and the mixture was shaken gently over-
night. After filtering off the resin, the filtrate was concentrated to
1454, 1437, 1260, 1212, 1156, 1044 cm–1. 1H NMR ([D6]DMSO,
400 MHz): δ = 8.99 (t, J = 6.1 Hz, 1 H) 8.60 (d, J = 2.1 Hz, 1 H),
7.86 (dd, J = 9.1, 2.1 Hz, 1 H), 7.23 (t, J = 7.1 Hz, 1 H), 6.96–6.79
(m, 4 H), 4.63 (d, J = 6.1 Hz, 2 H), 3.70 (s, 3 H) ppm. 13C NMR
([D6]DMSO, 75 MHz): δ = 165.8, 159.5, 147.1, 139.5, 135.8, 130.8,
129.7, 128.3, 118.9, 117.4, 115.0, 112.7, 112.4, 56.0, 54 ppm.[33]
give 24 (3.2 mg, Ͼ99%) as a yellow solid. FTIR (ATR): ν = 3343,
˜
Acknowledgments
3101, 2902, 2855, 1675, 1614, 1563, 1537, 1437, 1364, 1277, 1230,
1152, 1083, 932, 759, 703, 543, 521 cm–1. 1H NMR ([D6]DMSO,
400 MHz): δ = 8.65 (t, J = 5.9 Hz, 1 H), 8.58 (d, J = 2.1 Hz, 1 H),
7.91 (dd, J = 9.0, 1.7 Hz, 1 H), 6.98 (d, J = 9.1 Hz, 1 H), 5.93–5.84
(m, 1 H), 5.21–5.13 (m, 2 H), 4.08–4.05 (m, 2 H) ppm. 13C NMR
([D6]DMSO, 75 MHz): δ = 165.8, 147.2, 135.7, 133.8, 130.5, 128.3,
117.1, 116.2, 115.0, 44.5 ppm.[33]
These investigations were supported (in part) by the Netherlands
Research Council for Chemical Sciences (CW) with financial aid
from the Netherlands Technology Foundation (STW).
[1] See, e.g.: a) Handbook of Combinatorial Chemistry (Eds.: K. C.
Nicolaou, R. Hanko, W. Hartwig), Wiley-VCH, Weinheim,
2002; b) Combinatorial Chemistry, 2nd revised ed. (Eds: W.
Bannwarth, B. Hinzen), Wiley-VCH, Weinheim, 2006.
[2] R. B. Merrifield, J. Am. Chem. Soc. 1963, 85, 2149–2154.
[3] G. R. Marshall, J. Pept. Sci. 2003, 9, 534–544.
[4] D. P. Curran, Angew. Chem. Int. Ed. 1998, 37, 1174–1196.
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[6] a) I. T. Horváth, J. Rábai, Science 1994, 266, 72–75; b) I. T.
Horváth, Acc. Chem. Res. 1998, 31, 641–650.
[7] a) D. P. Curran, M. Hoshino, J. Org. Chem. 1996, 61, 6480–
6481; b) D. P. Curran, S. Hadida, J. Am. Chem. Soc. 1996, 118,
2531–2531.
[8] A. M. Hay, S. Hobbs-Dewitt, A. A. MacDonald, R. Ramage,
Tetrahedron Lett. 1998, 39, 8721–8724.
[9] a) R. Ramage, G. Raphy, Tetrahedron Lett. 1992, 33, 385–388;
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1998, 39, 8715–8718.
[10] R. Ramage, F. O. Wahl, Tetrahedron Lett. 1993, 34, 7133–7136.
[11] S. Zhang, K. Fukase, S. Kusumoto, Tetrahedron Lett. 1999, 40,
7479–7483.
3-Nitro-4-(prop-2-ynylamino)benzoic Acid (25): Reaction of 20 ac-
cording to the general procedure with propargylamine provided 22.
FTIR (ATR): ν = 2954, 2924, 2868, 1718, 1692, 1649, 1619, 1571,
˜
1511, 1316, 1216, 1113, 1009, 910, 819, 806, 741 cm–1. 1H NMR
(CDCl3, 400 MHz): δ = 13.12 (s, 1 H), 12.32 (s, 1 H), 12.27 (s, 1
H), 8.91 (d, J = 1.7 Hz, 1 H), 8.43 (br. t, J = 5.3 Hz, 1 H), 8.14
(dd, J = 8.9, 1.4 Hz, 1 H), 7.72 (d, J = 8.3 Hz, 2 H), 7.41 (d, J =
7.7 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 2 H), 6.98 (d, J = 8.6 Hz, 2 H),
5.94 (s, 1 H), 5.29 (s, 2 H), 5.06 (s, 2 H), 4.17 (d, J = 5.7 Hz, 2 H),
2.37–2.32 (m, 2 H), 1.72–1.58 (m, 4 H), 1.35–1.24 (m, 4 H), 0.92
(t, J = 7.2 Hz, 3 H), 0.89 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 172.66, 164.53, 158.60, 155.49, 154.47,
146.29, 137.63, 136.32, 132.16, 130.26, 129.97, 129.17, 128.02,
120.73, 115.01, 114.88, 113.55, 106.48, 77.98, 72.94, 69.83, 67.68,
66.74, 45.59, 33.11, 32.94, 29.87, 29.52, 26.86, 22.70, 14.13,
11.96 ppm. HRMS (FAB): calcd. for C36H39N6O7 [M + H]+
667.2880, found 667.2876. Direct treatment of compound 22 with
TFA/H2O as described above, gave acid 25 in quantitative yield.
[12] S. D. Lepore, Tetrahedron Lett. 2001, 42, 6437–6439.
[13] S. V. Ley, A. Massi, F. Rodríguez, D. C. Horwell, R. A.
Lewthwaite, M. C. Pritchard, A. M. Reid, Angew. Chem. Int.
Ed. 2001, 40, 1053–1055.
[14] J. Siu, I. R. Baxendale, R. A. Lewthwaite, S. V. Ley, Org. Bi-
omol. Chem. 2005, 3, 3140–3160.
[15] C. Palomo, J. M. Aizpurua, I. Loinaz, M. J. Fernandez-Berridi,
L. Irusta, Org. Lett. 2001, 3, 2361–2364.
[16] S.-Q. Zhang, K. Fukase, M. Izumi, Y. Fukase, S. Kusumoto,
Synlett 2001, 590–596.
FTIR (ATR): ν = 3356, 3291, 3084, 2958, 2816, 1675, 1610, 1563,
˜
1532, 1433, 1411, 1273, 1217, 1156, 923, 764, 681, 646 cm–1. 1H
NMR ([D6]DMSO, 400 MHz): δ = 8.69 (t, J = 5.9 Hz, 1 H), 8.62
(d, J = 2.1 Hz, 1 H), 8.04 (dd, J = 9.0, 2.0 Hz, 1 H), 7.16 (d, J =
9.1 Hz, 1 H), 4.28 (dd, J = 5.9, 2.4 Hz 2 H), 3.25 (t, J = 2.4 Hz, 1
H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 165.8, 146.2, 135.9,
131.2, 128.2, 117.9, 115.0, 79.9, 74.3, 32.0 ppm. HRMS (FAB):
calcd. for C10H9N2O4 [M + H]+ 221.0562, found 221.0559.
4-[(4-Methoxybenzyl)amino]-3-nitrobenzoic Acid (26): Reaction of
20 according to the general procedure with (p-methoxybenzyl)-
[17] Y. Fukase, S.-Q. Zhang, K. Iseki, M. Oikawa, K. Fukase, S.
Kusumoto, Synlett 2001, 1693–1698.
amine provided 23. FTIR (ATR): ν = 3373, 3045, 2954, 2829, 1697,
˜
[18] S. K. Chang, A. D. Hamilton, J. Am. Chem. Soc. 1988, 110,
1318–1319.
1649, 1618, 1576, 1511, 1325, 1264, 1217, 1109, 1009, 910, 798,
737 cm–1. H NMR (CDCl3, 400 MHz): δ = 13.12 (s, 1 H), 12.31 [19] In ref.[17], Fukase describes that large apolar compounds could
1
not be abstracted from a solution in chloroform. A solvent
switch to toluene was necessary to obtain the product.
[20] S. H. M. Söntjens, R. P. Sijbesma, M. H. P. Van Genderen,
E. W. Meijer, J. Am. Chem. Soc. 2000, 122, 7487–7493.
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(s, 1 H), 12.27 (s, 1 H), 8.91 (d, J = 1.5 Hz, 1 H), 8.70 (br. t, J =
5.5 Hz, 1 H), 8.00 (dd, J = 9.0, 2.0 Hz, 1 H), 7.72 (d, J = 8.4 Hz,
2 H), 7.40 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.5 Hz, 2 H), 7.30–
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(s, 1 H), 5.26 (s, 2 H), 5.05 (s, 2 H), 4.55 (d, J = 5.6 Hz, 2 H), 3.79
(s, 3 H), 2.38–2.32 (m, 1 H), 1.75–1.58 (m, 4 H), 1.43–1.24 (m, 4
H), 0.92 (t, J = 7.3 Hz, 3 H), 0.88 (t, J = 7.2 Hz, 3 H) ppm. 13C
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Received: March 16, 2007
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4204
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Eur. J. Org. Chem. 2007, 4197–4204