Synthesis of novel dendrimeric systems containing NLO ligands

Article abstract of DOI:10.1002/ejoc.200400609

The convergent synthesis of novel dendrimeric systems containing NLO-ligands is described. The poor solubility properties of dendrimers of type A containing NLO-ligands enticed us into developing novel dendrimers of type B leading to the convergent synthesis of third generation NLO-containing dendrimer 15 containing branches of unequal length. Furthermore, a strategy was developed for connection of dendrons leading to dendrimer-to-dendrimer systems of type C. For this a dendrimer was required of which selectively one branch could be deprotected i.e. dendrimer 22. To the deprotected branch a next dendrimer moiety was attached leading to 23, also containing a deprotectable branch, which was used for attachment of another dendrimer moiety, leading to dendrimer-to- dendrimer system 24. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400609

FULL PAPER
Synthesis of Novel Dendrimeric Systems Containing NLO Ligands
Arwin J. Brouwer[a] and Rob M. J. Liskamp*[a]
Keywords: Dendrimers / Amides / Amino acids / Synthesis design
The convergent synthesis of novel dendrimeric systems con-
taining NLO-ligands is described. The poor solubility proper-
ties of dendrimers of type A containing NLO-ligands enticed
us into developing novel dendrimers of type B leading to the
convergent synthesis of third generation NLO-containing
dendrimer 15 containing branches of unequal length.
Furthermore, a strategy was developed for connection of
dendrons leading to dendrimer-to-dendrimer systems of type
C. For this a dendrimer was required of which selectively
one branch could be deprotected i.e. dendrimer 22. To the
deprotected branch a next dendrimer moiety was attached
leading to 23, also containing a deprotectable branch, which
was used for attachment of another dendrimer moiety, lead-
ing to dendrimer-to-dendrimer system 24.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
to novel dendrimer systems B and “dendrimer-to-den-
drimer” systems C.
Introduction
As dendrimers possess – dependent on the generation –
several branch-ends[1], we have been interested in using
these macromolecular systems for organization and simul-
taneous presentation of several functional ligands. This has
led among others to dendrimeric multivalent systems con-
taining carbohydrate ligands, which can interact with
carbohydrate binding proteins, showing significant en-
hancement of the binding affinity of these compounds as
compared to the individual carbohydrate moieties.[2] As a
result, multivalent dendrimeric systems containing carbo-
hydrates capable of interacting with bacterial toxins, might
be attractive for new approaches towards new antibiotics
in which development of resistance by pathogens might be
avoided. In addition to presenting several copies of a par-
ticular ligand, dendrimers might provide molecular scaf-
folds for spatially organizing ligands, so that binding prop-
erties or other individual molecular ligand-properties may
be enhanced. However, we found that the “covalent organi-
zation” capacity of our amino acid based dendrimers[3] e.g.
A (Figure 1) is fairly limited and Langmuir monolayer stud-
ies showed that the branches of these dendrimers tend to
spread out.[4]
Results and Discussion
Initially, we had planned to prepare NLO-group contain-
ing dendrimers based on monomer 4 since this can be pre-
pared from building block 3 which on its turn can be easily
synthesized on a large scale from 3,5-dihydroxybenzoic acid
and Boc-2-bromoethylamine (Scheme 1). This building
block has two identical “branches” and has been used in
the preparation of the amino acid-based dendrimers[3] in-
troduced by us. After removal of the Boc-groups in 3, the
4-nitrophenyl group was introduced in a nucleophilic aro-
matic substitution reaction with 1-fluoro-4-nitrobenzene in
DMSO and Et3N as a base. Unfortunately, NLO monomer
4 was poorly soluble in common organic solvents, probably
because of aromatic π-stacking. This poor solubility pre-
cluded synthesis of the second generation dendrimer based
on monomers 3 and 4. In order to improve the solubility –
by preventing π-stacking of the aromatic rings –, it was de-
cided to prepare a NLO monomer with “branches” of dif-
ferent lengths i.e. containing an ethyl and a propyl branch.
The synthesis of this NLO-group containing monomer 8
started with mono-alkylation of 3,5-dihydroxybenzoic acid
with 0.5 equiv. of Boc-2-bromoethylamine (2) in dimethyl-
formamide. As expected the reaction afforded a mixture of
mono-alkylated product 5, di-alkylated product 3, and un-
reacted 3,5-dihydroxybenzoic acid (1). After tedious purifi-
cation, by four subsequent silica gel columns, the mono-
alkylated product 5 was obtained in 26 % yield. The unre-
acted 3,5-dihydroxybenzoic acid could be re-used, and the
di-alkylated product 3 was used in later steps of the synthe-
sis of the NLO-group containing dendrimers (vide infra,
Scheme 2). Alkylation of 5 with mesylate 6 in dimethylfor-
Next to biologically relevant ligands, dendrimers might
be used for organization of ligands crucial in the determi-
nation of certain material properties.[1,5]
In this paper we have explored the possibilities of synthe-
sizing dendrimers containing a relatively simple NLO[6]
(nonlinear optical) moiety based on the earlier developed
amino acid based dendrimers such as A (Figure 1), leading
[a]
Department of Medicinal Chemistry, Utrecht Institute for
Pharmaceutical Sciences, Utrecht University,
P. O. Box 80082, 3508 TB Utrecht, The Netherlands
Fax: (internat.) +31-30-253-6655
E-mail: r.m.j.liskamp@pharm.uu.nl
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DOI: 10.1002/ejoc.200400609
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Figure 1. Earlier developed amino acid-based dendrimer A[3] and novel dendrimeric systems B and C
mamide afforded the Boc-protected monomer 7. Boc-de- equivalents of “surface” monomer 13 and one equivalent
protection followed by reaction with 1-fluoro-4-nitroben- of “branching” monomer 12. Saponification of the methyl
zene provided NLO monomer 8 in 73 % yield. As the solu- ester of the resulting second generation dendrimer 14, fol-
bility of 8 was only slightly better than the solubility of lowed by coupling to “branching” monomer 12, afforded
monomer 4, it was decided to prepare a monomer with a third generation dendrimer 15 in 65 % yield. The latter reac-
much larger difference in the lengths of the “branches”, and tion was carried out using the higher boiling acetonitrile
branches containing two and twelve carbon atoms were se- compared to dichloromethane, which also gave a more
lected. To this end, 5 was alkylated with mesylate 9, afford- homogeneous reaction mixture. Although, third generation
ing Boc-protected monomer 10 in 85 % yield. After depro- dendrimer 15 was very poorly soluble in most organic sol-
tection of the amino groups, the substitution reaction with vents, it still could be purified by column chromatography
1-fluoro-4-nitrobenzene, was cumbersome compared to using methanol/dichloromethane mixtures. However, de-
other similar substitution reactions (to, 4 and 8). Optimiza- spite apparent formation of the fourth generation NLO-
tion, using dimethylacetamide as a solvent and DiPEA as group containing dendrimer – according to TLC – attempts
a base instead of DMSO and Et3N led to an improved pro- to obtain the pure compound failed due to now an almost
cedure affording 11 in 68 % yield. Indeed, this NLO mono- insoluble crude product.
mer had a much better solubility in most organic solvents
In order to obtain a “dendrimer-to-dendrimer” system
than 4 or 8.
as is schematically represented in Figure 1 (C), which might
This monomer was now suitable for the preparation of be also favorable for alignment of the NLO endgroups, den-
higher generations of NLO containing dendrimers drimers are called for containing one – protected – amino
(Scheme 2). Two types of monomers were needed: “surface” group, which could be used for connecting the next den-
monomer 13, which was obtained by saponification of drimer system. For the preparation of such a dendrimer,
methyl ester 11, and “branching” monomer 12,[3c] which a “surface” monomer was required viz. 19 having one 4-
was obtained by Boc-group removal of monomer 3. Second nitrophenyl-group and one Boc-protected amine, that was
generation dendrimer 14 was synthesized in 84 % yield by synthesized starting from methyl-3,5-dihydroxybenzoic acid
a peptide-amide coupling reaction, with BOP using two (1, Scheme 3). Monoalkylation with Cbz-2-bromoethyl-
488
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Novel Dendrimeric Systems Containing NLO Ligands
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Scheme 1
Scheme 2
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A. J. Brouwer, R. M. J Liskamp
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amine (17), afforded the mono-alkylated product in only 14 % the construction of dendrimer-to-dendrimer systems. To
yield after a tedious purification. Fortunately, monoalkyl- this end, 22 was Boc-deprotected to afford the “core” den-
ation of 1 with mesylate 9 gave compound 16 in 39 % yield, drimer, and 22 was saponified affording the “surface” den-
which was clearly better than the monoalkylation reaction drimer (Scheme 5). Coupling of these dendrimers, using
and subsequent purfication in the preparation of 5 (26 %), BOP, DiPEA and acetonitrile, afforded dendrimer-to-den-
and therefore an attractive alternative for a future synthesis drimer 23 in 62 % yield. This dendrimer system was still
of 10 (Scheme 1). Next, alkylation with Cbz-2-bromoethyla- very soluble in dichloromethane/methanol mixtures, and
mine 17 gave monomer 18 (88 %), of which the Cbz-group could be easily purified by column chromatography. Be-
was cleaved by hydrogenolysis in the presence of chloroform cause of its solubility, it was also possible to couple a subse-
to give the hydrochloride salt, which was immediately con- quent dendrimer to it. Therefore, the Boc-group was cleaved
verted into “surface” NLO monomer 19 in 82 % yield by a from dendrimer 23 and BOP-coupling of saponified den-
substitution reaction with 1-fluoro-4-nitrobenzene. In this drimer 22 gave dendrimer-to-dendrimer system 24 in 30 %
monomer the Boc-group was deliberately attached to the yield. This dendrimer had still similar solubility properties
amine functionality of the longest “branch” to prevent pos- as dendrimer 23.
sible steric hindrance during coupling of the dendrimer sys-
tems to each other.
Scheme 3
The other required monomer was “branching” monomer
20 (Scheme 3). This monomer was obtained after alkylation
of mono-alkylated monomer 5 with Cbz-2-bromoethylam-
ine 17 in 89 % yield. After removal of the Cbz-group in
Scheme 4
“branching” monomer 20, monomer 13 was coupled in a
BOP coupling, yielding dendrimer-half 21 (Scheme 4). Syn-
thesis to give the “complete” second generation dendrimer
system 22, was achieved after Boc-cleavage and coupling
with saponified “surface” monomer (19) in 76 % yield.
Conclusions
Attempts to synthesize the third generation dendrimer con-
We have synthesized dendrimers with “unequal”
taining seven p-nitrophenyl groups and one Boc-group were branches, thereby successfully coping with the insolubility
carried out by coupling of Cbz-deprotected 20 with sapon- of the earlier dendrimeric systems caused by the aromatic
ified second generation NLO-group containing dendrimer NLO ligands. Although, the dendrimers by themselves may
14, followed by Boc-deprotection and coupling with sapon- organize the NLO ligands, which might be favorable for op-
ified 22. Unfortunately, a very poor solubility and insepa- tical properties, we developed an alternative dendrimer-to-
rable impurities impeded with its purification. Therefore, it dendrimer system. This elongated system had good solubil-
was decided to use only second generation dendrimer 22 for ity properties and might provide additional organization of
490
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Novel Dendrimeric Systems Containing NLO Ligands
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Scheme 5
trometer coupled with a HP-9000 data system. Electrospray mass
spectra were recorded with a Shimadzu LCMS-QP-8000 spectrom-
eter, or with a Fisons VG Platform II Single quadrupole mass spec-
trometer (Micromass, Manchester, UK).
dendrimeric ligands. Studies of the optical properties of
these novel dendrimeric systems, possibly reflecting their
organization capacities, will be reported in due course.
Mono-Alkylated Monomer 5: A mixture of methyl 3,5-dihydroxy-
benzoate (1) (20.1 g, 120 mmol), K2CO3 (16.6 g, 120 mmol) and
dry dimethylformamide (560 mL) was stirred at room temp. for 1h.
A solution of 2-Boc-aminoethyl bromide (60 mmol) in dimethylfor-
mamide (40 mL) was added in four equal portions with 30 min of
stirring after each addition. The temperature was raised to 40 °C
and the mixture was stirred for two days. After filtration through
Hyflo, the dimethylformamide was evaporated in vacuo. The resi-
due was dissolved in ethyl acetate and washed with water (twice)
and brine. The organic layer was dried with Na2SO4, and concen-
trated. After addition of dichloromethane (200 mL), the flask was
rotated at 40 °C (waterbath) for 30 min, giving a precipitate, wich
was removed by filtration. The solution was concentrated and puri-
fied by column chromatography (4 times, 4 % acetone/DCM). After
the purification, wich was very tedious due to contaminations of
non- and di-alkylated products, the product was obtained as a
white solid (4.9 g, 26 %). Rf = 0.68 (EtOAc/hexanes, 1:1). M.p.
Experimental Section
General Remarks: Unless stated otherwise, chemicals were obtained
from commercial sources and used without further purification.
Solvents were dried on molecular sieves (4 Å). Slightly modified
Tesser’s base used for saponifications was a mixture of dioxane,
MeOH and 4 m NaOH (14:5:2, v/v/v).[7] TLC analysis was per-
formed on Merck precoated 60 F-254 (0.25 mm) plates. Spots were
visualized with UV light and ninhydrine. Solvents were evaporated
under reduced pressure at 40 °C. Column chromatography was per-
formed on Merck Kieselgel 60 (40–63 µm), all eluents are given in
v/v. All dendrimers – except first generation dendrimers –, were
purified by column chromatography, using a 18 cm silica column,
with a diameter depending on the amount of crude dendrimer. For
1 g crude material a 3-cm diameter column was used. Elemental
analyses were carried out at Kolbe Mikroanalytisches Laborato-
rium (Mülheim an der Ruhr, Germany). H NMR (300 MHz), 13C
1
1
107 °C. H NMR (CDCl3): δ = 1.46 [s, 9 H, C(CH3)3], 3.52 (m, 2
NMR (75 MHz) and COSY spectra were recorded with a Varian
G-300 spectrometer. 1H NMR (500 MHz), COSY and HMBC
spectra of 24 were recorded with a Varian Inova-500 spectrometer.
Chemical shifts are reported in ppm relative to TMS (δ = 0 ppm)
H, NHCH2), 3.89 (s, 3 H, OCH3), 4.02 (t, 2 H, OCH2, J = 5.1 Hz),
5.02 (br. s, 1 H, NHBoc), 6.28 (br. s, 1 H, OH), 6.61 (s, 1 H, Ph
C4-H), 7.14 (m, 2 H, Ph C2,6-H) ppm. 13C NMR (CDCl3): δ =
28.4 [C(CH3)3], 40.1 (NHCH2), 52.3 (OCH3), 67.3 (OCH2), 80.1
[C(CH3)3], 106.9, 107.5, 109.7 (Ph C2,4,6), 132.0 (Ph C1), 156.3
[C=O (Boc)], 157.5, 159.7 (Ph C3,5), 167.0 (CO2Me) ppm. MS
(ESI): m/z = 334.1 [M + Na]+. C15H21NO6 (311.33): calcd. C 57.87,
H 6.80, N 4.50; found C 57.73, H 6.68, N 4.49.
1
or [D6]DMSO (δ = 2.50 ppm) for the H NMR, and CDCl3 (δ =
77 ppm), [D6]DMSO (δ = 39.5 ppm) or CD3OD (δ = 49 ppm) for
the 13C NMR as internal standards. C4-H: denotes a proton of the
first generation; C4Ј-H: denotes a proton of the second generation
etc.; C4Ј,4ЈЈ: denotes carbon atoms of the first and second genera-
tion. Ar denotes the p-nitroaromatic rings; Ph denotes the 3,5-dihy-
droxybenzoic acid based aromatic rings. MS (FAB) mass spectra
were measured with a Jeol JMS SX/SX 102A four-sector mass spec-
3-Boc-aminopropylmesylate (6): 3-Aminopropanol (22.9 mL,
300 mmol) was dissolved in dichloromethane (175 mL). After cool-
ing to 0 °C di-tert-butyl dicarbonate (65.5 g, 300 mmol) in dichlo-
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romethane (50 mL) was added dropwise. The reaction was stirred
at room temp. for 5.5 h. After addition of more dichloromethane,
the mixture was washed with water and brine, dried (Na2SO4) and
concentrated in vacuo. 3-Boc-aminopropanol was obtained as a
colorless oil (49.4 g, 94 %). Rf = 0.47 (diethylether). 1H NMR
Mesylate 9: Mesylate 9 was prepared from 12-aminododecanoic
acid by esterification, Boc-protection, reduction and mesylation,
affording a white solid (87 %, 4 steps)[3c]. Rf = 0.77 (EtOAc/hex-
anes, 1:1). M.p. 47 °C. 1H NMR (CDCl3): δ = 1.27–1.44 [m, 27 H,
C(CH3)3, NHCH2(CH2)9], 1.74 (m, 2 H, OCH2CH2), 3.00 (s, 3 H,
(CDCl3): δ = 1.44 [s, 9 H, C(CH3)3], 1.67 (m, 2 H, CH2CH2CH2), CH3SO3), 3.10 (m, 2 H, NHCH2), 4.22 (t, 2 H, OCH2, J = 6.6 Hz),
2.97 (br. s, 1 H, OH), 3.28 (m, 2 H, CH2NH), 3.66 (br. s, 2 H,
4.48 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3): δ = 25.3, 26.7, 28.9,
OCH2), 4.78 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3): δ = 28.3 29.0, 29.2, 29.3 (2 ×), 29.4, 30.0 [NHCH2(CH2)10], 28.3 [C(CH3)3],
[C(CH3)3], 32.6 (CH2CH2CH2), 37.0 (CH2NH), 59.3 (OCH2), 79.4 37.3 (OCH3), 40.5 (NHCH2), 70.1 (OCH2), 78.9 [C(CH3)3], 155.9
[C(CH3)3], 157.0 [C=O (Boc)] ppm.
[C=O (Boc)] ppm. MS (ESI): m/z = 402.3 [M + Na]+. C18H37NO5S
(379.56): calcd. C 56.96, H 9.83, N 3.69; found C 56.83, H 9.75, N
3.73.
To a cooled solution (ice-bath) of 3-Boc-aminopropanol (2.60 g,
14.8 mmol) and methanesulfonyl chloride (1.28 mL, 16.5 mmol) in
dichloromethane (13 mL) was slowly added triethylamine (2.3 mL,
16.5 mmol). After stirring for 1 h, the reaction mixture was concen-
trated and dissolved in ethyl acetate. The solution was washed with
1 m KHSO4, water (twice) and brine, dried (Na2SO4) and concen-
trated in vacuo. The mesylate was obtained as a yellow solid
(3.41 g, 91 %), and was directly used without further purification
in the synthesis of monomer 7. Rf = 0.62 (EtOAc/hexanes, 1:1).
Monomer 10: A mixture of 5 (1.12 g, 3.6 mmol), K2CO3 (2.24 g,
16.2 mmol), mesylate 9 (1.38 g, 3.96 mmol) and dimethylfor-
mamide (7.2 mL) was stirred at 40 °C for 6 days. The mixture was
filtered over Hyflo, and the solvent was removed in vacuo. After
adding ethyl acetate, the mixture was washed with water (twice)
and brine, dried and concentrated. Column chromatography
(EtOAc/hexanes, 3:7) afforded monomer 10 as a clear colorless oil
Monomer 7: A mixture of 5 (2.02 g, 6.5 mmol), potassium carbon-
ate (2.02 g, 14.6 mmol), mesylate 6 (2.14 g, 8.45 mmol) and di-
methylformamide (13 mL) was stirred for three days at 40 °C. The
reaction mixture was cooled to room temp. and filtered over Hyflo.
After evaporation of the solvent in vacuo, the residue was dissolved
in ethyl acetate and water. The organic layer was washed with water
and brine, dried (Na2SO4) and concentrated. Column chromatog-
raphy (EtOAc/hexanes, 3:7) afforded the product as a white foam
(2.07 g, 68 %). Rf = 0.18 (EtOAc/hexanes, 3:7). 1H NMR (CDCl3):
δ = 1.45 (s, 18 H, 2 × C(CH3]3), 2.00 (m, 2 H, OCH2CH2CH2),
3.32 (m, 2 H, NHCH2CH2CH2), 3.54 (m, 2 H, NHCH2CH2O),
3.90 (s, 3 H, OCH3), 4.04 (m, 4 H, 2 × OCH2), 4.72 [br. s, 1 H,
NH(CH2)3O], 4.96 [br. s, 1 H, NH(CH2)2O], 6.64 (m, 1 H, Ph C4-
H), 7.18 (m, 2 H, Ph C2,6-H) ppm. 13C NMR (CDCl3): δ = 28.4
[C(CH3)3], 29.5 (OCH2CH2CH2), 37.9 (NHCH2CH2CH2), 40.1
(NHCH2CH2O), 52.2 (OCH3), 66.1 [OCH2(CH2)2], 67.5
(OCH2CH2NH), 79.2, 79.6 [C(CH3)3], 106.6, 107.9, 108.1 (Ph
C2,4,6), 132.1 (Ph C1), 155.8, 156.0 [C=O (Boc)], 159.6, 159.8 (Ph
C3,5-H), 166.6 (CO2Me) ppm.
1
(1.8 g, 85 %). Rf = 0.26 (EtOAc/hexanes, 3:7). H NMR (CDCl3):
δ = 1.26–1.44 [m, 36 H, 2 × C(CH3)3, 2 × NHCH2(CH2)9], 1.75
[m, 2 H, OCH2CH2(CH2)10], 3.09 [m, 2 H, NHCH2(CH2)11], 3.52
(m, 2 H, NHCH2CH2O), 3.89 (s, 3 H, OCH3), 3.96 [t, J = 6.6 Hz,
2 H, OCH2(CH2)11], 4.03 (t, J = 5.0 Hz, 2 H, OCH2CH2NH), 4.51
[br. s, 1 H, NH(CH2)12], 4.99 [br. s, 1 H, NH(CH2)2O], 6.63 (m, 1
H, Ph C4-H), 7.16 (m, 2 H, Ph C2,6-H) ppm. 13C NMR (CDCl3):
δ = 25.8, 26.6, 29.0, 29.1 (2 ×), 29.3, 29.9 [NHCH2(CH2)10], 8.2,
28.3 [C(CH3)3], 39.9 (NHCH2CH2O), 40.5 [NHCH2(CH2)11], 52.0
(OCH3), 67.3 (OCH2CH2NH), 68.2 [OCH2(CH2)11], 78.7, 79.2
[C(CH3)3], 106.4, 107.5, 108.0 (Ph C2,4,6), 131.8 (Ph C1), 155.7,
155.9 [C=O (Boc)], 159.4, 160.0 (Ph C3,5), 166.5 (CO2Me) ppm.
MS (ESI): m/z = 595.4 [M + H]+, 617.6 [M + Na]+. C32H54N2O8
(594.78): calcd. C 64.62, H 9.15, N 4.71; found C 64.75, H 9.22, N
4.59.
NLO Monomer 11: Monomer 10 was Boc-deprotected following
the procedure as described in the synthesis of 8, affording the hy-
drochloride salt as a white solid (1.33 g, 95 %). A mixture of the
hydrochloride salt (1.28 g, 2.75 mmol), 1-fluoro-4-nitrobenzene
(642 µL, 6.05 mmol), dimethylacetamide (14 mL) and diisopropyl-
NLO Monomer 8: To a solution of 7 (1.98 g, 4.23 mmol) in dry
dichloromethane (10 mL), was added diethylether (20 mL), satu-
rated with HCl. After stirring for 35 min, the mixture was concen- ethylamine (1.91 mL, 11.0 mmol) was stirred at 100 °C overnight.
trated in vacuo, and the residue was dried with KOH overnight.
The hydrochloride salt was obtained as a white solid (1.42 g, 99 %).
A mixture of the hydrochloride salt (171 mg, 0.50 mmol), 1-fluoro-
4-nitrobenzene (117 µL, 1.1 mmol), dimethyl sulfoxide (2.5 mL)
and triethylamine (313 µL, 2.25 mmol) was refluxed overnight. Af-
ter cooling to room temp., ethyl acetate (15 mL) was added and
the mixture was washed with 1m KHSO4, water (twice) and brine.
The organic layer was dried (Na2SO4) and concentrated in vacuo.
Crystallization (DMSO/MeOH) afforded the product as a yellow
solid (188 mg, 74 %). Rf = 0.47 (EtOAc/hexanes, 3:7). M.p. 152 °C.
After cooling to room temp., ethyl acetate (90 mL) was added and
the mixture was washed with 1 m KHSO4, water and brine. The
organic layer was dried (Na2SO4) and concentrated in vacuo. Col-
umn chromatography (hexanes/DCM, 6:94) followed by crystalliz-
ation (EtOAc/hexanes) afforded the product as a yellow solid
(1.26 g, 72 %). Rf = 0.54 (EtOAc/hexanes, 1:1). M.p. 93 °C. 1H
NMR (CDCl3): δ = 1.30 [m, 16 H, NHCH2CH2(CH2)8], 1.64 [m,
2 H, NHCH2CH2(CH2)10], 1.77 [m, 2 H, OCH2CH2(CH2)10], 3.21
[m, 2 H, NHCH2(CH2)11], 3.65 (m, 2 H, NHCH2CH2O), 3.91 (s, 3
H, OCH3), 3.97 [t, J = 6.2 Hz, 2 H, OCH2(CH2)11], 4.22 (t, J =
1H NMR ([D6]DMSO): δ = 1.95 (m, 2 H, OCH2CH2CH2), 3.25 5.0 Hz, 2 H, OCH2CH2NH), 4.47 [br. s, 1 H, NH(CH2)12], 4.86 [br.
(m, 2 H, NHCH2CH2CH2), 3.50 (m, 2 H, NHCH2CH2O), 3.76 (s, s, 1 H, NH(CH2)2O], 6.52, 6.62 (2d, J = 9.2, J = 9.1 Hz, 4 H, 2 ×
3 H, OCH3), 4.03, 4.13 (2 m, 4 H, 2 × OCH2), 6.58, 6.66 (2d, J = Ar C2,6-H), 6.65 (m, 1 H, Ph C4-H), 7.22, 7.26 (2br. s, 2 H, Ph C2,6
-
9.5, J = 9.5 Hz, 4 H, 2 × Ar C2,6-H), 6.73 (s, 1 H, Ph C4-H), 7.01
(m, 2 H, Ph C2,6-H), 7.25, 7.37 (2br. s, 2 H, 2 × NH), 7.92 (m, 4
H, 2 × Ar C3,5-H) ppm. 13C NMR ([D6]DMSO): δ = 28.0
(OCH2CH2CH2), 40.4, 41.9 (NHCH2), 52.3 (OCH3), 65.6, 66.7
(OCH2), 106.4, 107.6, 107.7 (Ph C2,4,6), 111.0 (Ar C2,6), 126.2, 126.3
(Ar C3,5), 131.7 (Ph C1), 135.8, 136.0 (Ar C1), 154.5, 154.6 (Ar C4),
159.6, 159.8 (Ph C3,5-H), 166.0 (CO2Me) ppm. MS (ESI): m/z =
511.4 [M + H]+, 533.9 [M + Na]+. C25H26N4O8 (510.50): calcd. C
58.82, H 5.13, N 10.98; found C 58.88, H 5.19, N 10.85.
H), 8.10 (m, 4 H, Ar C3,5-H) ppm. 13C NMR (CDCl3): δ = 25.9,
26.9, 29.1, 29.2, 29.3, 29.5, 29.7 [NHCH2(CH2)10], 42.6
(NHCH2CH2O), 43.4 [NHCH2(CH2)11], 52.3 (OCH3), 66.3
(OCH2CH2NH), 68.4 [OCH2(CH2)11], 106.7 (Ph C4), 107.4, 108.5
(Ph C2,6) 110.9, 111.3 (Ar C2,6), 126.3, 126.4 (Ar C3,5), 132.1 (Ph
C1), 137.7, 138.4 (Ar C1), 153.0, 153.5 (Ar C4), 159.2, 160.3 (Ph
C3,5), 166.7 (CO2Me) ppm. MS (FAB): m/z = 637.5 [M + H]+.
C34H44N4O8 (636.74): calcd. C 64.13, H 6.97, N 8.80; found C
64.20, H 6.92, N 8.71.
492
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 487–495

Novel Dendrimeric Systems Containing NLO Ligands
FULL PAPER
Dendrimer 14: A solution of monomer 11 (1.02 g, 1.60 mmol) in
slightly modified Tesser’s base (18 mL), was stirred for 2 h at room
131.6 (Ph C1), 135.4, 135.9, 136.2, 136.3 (Ph C1Ј,1ЈЈ, Ar C1), 154.4,
154.5 (Ar C4), 159.3, 159.4, 159.6, 159.7 (Ph C3,5,3Ј,5Ј,3ЈЈ,5ЈЈ), 165.7,
temp. The pH was adjusted to approximately 2 with 1 m KHSO4 165.9, 166.0 (CO2CH3, NHC=O, NЈHC=O) ppm. MS (FAB): m/z
and the mixture was concentrated in vacuo. The residue was dis-
solved in ethyl acetate and water. The organic layer was washed
with water and brine, dried (Na2SO4) and concentrated in vacuo.
The acid was obtained as a yellow solid (966 mg, 97 %). To a
suspension of the acid (810 mg, 1.30 mmol), hydrochloride salt
12[3c] (213 mg, 0.65 mmol) and BOP (630 mg, 1.43 mmol) in dry
dichloromethane (6.5 mL) was slowly added DiPEA (736 µL,
4.23 mmol). The mixture was stirred at room temp. for 4 h, and
concentrated in vacuo. The residue was dissolved in dichlorometh-
ane and washed with water and brine, dried (Na2SO4) and concen-
trated to dryness. Column chromatography (MeOH/DCM, 2:98)
afforded second generation dendrimer 14 as a yellow foam (801 mg,
84 %). Rf = 0.67 (MeOH/DCM, 1:9). M.p. 46 °C. 1H NMR
(CDCl3): δ = 1.27–1.37 [m, 32 H, 2 × NHCH2CH2(CH2)8], 1.58–
1.68 [m, 4 H, 2 × NHCH2CH2(CH2)10], 1.71–1.76 [m, 4 H, 2 ×
OCH2CH2(CH2)10], 3.18 [m, 4 H, 2 × NHCH2(CH2)11], 3.59 (m, 4
= 3115.6 [M]+. C166H206N22O38 (3117.54): calcd. C 63.95, H 6.66,
N 9.88; found C 64.08, H 6.60, N 9.75.
Mono-Alkylated Monomer 16: The preparation of monomer 16 was
performed following the procedure described for the synthesis of 5,
on a 1.0 mmol scale. The reaction mixture was stirred for three
days at 40 °C, and cooled to room temp. After workup, the residue
was purified by column chromatography (EtOAc/hexanes, 2:8) af-
fording white crystalline discs (87.5 mg, 39 %). Rf = 0.46 (EtOAc/
hexanes, 3:7). M.p. 51 °C. 1H NMR (CDCl3): δ = 1.18–1.45 [m, 27
H, OCH2CH2(CH2)9, C(CH3)3], 1.74 (m, 2 H, OCH2CH2, 3.10 (m,
2 H, NHCH2), 3.88 (s, 3 H, OCH3), 3.95 (t, J = 6.4 Hz, 2 H,
OCH2), 4.63 (br. s, 1 H, NH), 6.64 (m, 1 H, Ph C4-H), 7.14 (m, 2
H, Ph C2,6-H), 7.19 (br. s, 1 H, OH) ppm. 13C NMR (CDCl3): δ =
25.9, 26.7, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 30.0 [OCH2(CH2)10],
28.4 [C(CH3)3], 40.7 (NHCH2), 52.1 (CH3), 68.3 (OCH2), 79.5
[C(CH3)3], 107.2, 107.4, 109.2 (Ph C2,4,6), 131.9 (Ph C1), 156.4
[C=O (Boc)], 157.5, 160.4 (Ph C3,5), 167.1 (CO2Me) ppm. MS
(ESI): m/z = 352.3 [M – Boc + H]+ , 474.5 [M + Na]+. C25H41NO6
(451.60): calcd. C 66.49, H 9.15, N 3.10; found C 66.57, H 9.22, N
3.06.
H,
2 × ArNHCH2CH2O), 3.81 [m, 4 H, 2 × PhC(O)
NHCH2CH2O], 3.87 (s, 3 H, OCH3), 3.91 (t, J = 6.5 Hz, 4 H, 2 ×
OCH2(CH2)11), 4.10 (t, J = 5.0 Hz, 4 H, 2 × OCH2CH2NHC=O),
4.15 (t, J = 5.2 Hz, 4 H, 2 × OCH2CH2NHAr), 4.65 [bt, 2 H, 2 ×
NH(CH2)12], 5.12 [m, 2 H, 2 × ArNH(CH2)2O], 6.47–6.60 (m, 11
H, 4 × Ar C2,6-H, Ph C4-H, 2 × Ph C4Ј-H), 6.75 (bt, 2 H, 2 ×
NHC=O), 6.88, 6.93 (2 m, 4 H, 2 × Ph C2Ј,6Ј-H), 7.14 (d, 2 H, Ph
C2,6-H), 8.04 (m, 8 H, 4 × Ar C3,5-H) ppm. 13C NMR (CDCl3): δ
= 25.9, 26.9, 29.0, 29.1, 29.2, 29.4, 29.7, [NHCH2(CH2)10], 39.6
[PhC(O)NHCH2] 42.6 (ArNHCH2CH2O), 43.4 [NHCH2(CH2)11],
52.3 (OCH3), 66.3 (OCH2CH2NHAr), 67.0 (OCH2CH2NHC=O),
68.4 [OCH2(CH2)11], 104.7, 105.2, 106.3, 108.3 (Ph C2,4,6,2Ј,4Ј,6Ј),
110.9, 111.3 (Ar C2,6), 126.3, 126.4 (Ar C3,5), 132.2 (Ph C1), 136.4
(Ph C1Ј), 137.6, 138.2 (Ar C1), 153.1, 153.6 (Ar C4), 159.5, 160.5
(Ph C3,5,3Ј,5Ј), 166.5 (CO2Me), 167.5 (NHC=O) ppm. MS (FAB):
m/z = 1463.9 [M + H]+. C78H98N10O18 (1463.67): calcd. C 64.01,
H 6.75, N 9.57; found C 64.24, H 6.41, N 9.36.
2-Cbz-aminoethyl Bromide (17): To a cooled (ice-bath) solution of
aminoethyl bromide·HBr (20.5 g, 100 mmol) and 2 m NaOH
(100 mL, 200 mmol) in dioxane (100 mL), was added Cbz-chloride
(14.3 mL, 100 mmol) dropwise. The temperature was raised to
room temp. and the mixture was stirred overnight. The mixture
was concentrated to dryness and dissolved in ethyl acetate and 1 m
KHSO4. The organic layer was washed with water (twice) and
brine, dried and concentrated. A silica gel plug (EtOAc/hexanes,
1:9) afforded the bromide as a white crystalline solid (23.1 g, 90 %).
1
Rf = 0.37 (EtOAc/hexanes, 2:8). H NMR (CDCl3): δ = 3.48 (t, 2
H, BrCH2), 3.61 (m, 2 H, NHCH2), 5.13 (s, 2 H, ArCH2), 5.18 (br.
s, 1 H, NH), 7.37 (m, 5 H, C6H5) ppm. 13C NMR (CDCl3): δ =
32.3 (BrCH2), 42.7 (NHCH2), 66.9 (ArCH2), 128.1, 128.2, 128.5
(Ar C2–6), 136.2 (Ar C1), 155.2 (C=O (Cbz) ppm.
Dendrimer 15: Second generation dendrimer 14 (110 mg, 75.0
µmol) was saponified following the procedure described in the syn-
thesis of 14, affording the acid as a yellow foam (108 mg, 99 %).
To a mixture of the acid (116 mg, 79.8 µmol), hydrochloride salt
12 (13.1 mg, 40.0 µmol), BOP (38.7 mg, 87.9 µmol) and acetonitrile
(0.4 mL) was added DiPEA (45.2 µL, 0.259 mmol) at room temp.
The mixture was refluxed for 4 h, cooled to room temp. and con-
centrated in vacuo. The residue was dissolved in dichloromethane
and washed with 1 m KHSO4 (twice), 1 m NaOH (twice) and brine.
Crystallization out of the organic layer afforded yellow needles
(40.3 mg). Column chromatography (MeOH/DCM, 3:97) from the
mother liquor afforded the product as a yellow foam (41.6 mg),
giving a total yield of 66 % (81.9 mg). Rf = 0.61 (MeOH/DCM,
Monomer 18: A mixture of 16 (497 mg, 1.10 mmol), bromide 17
(369 mg, 1.43 mmol), K2CO3 (342 mg, 2.47 mmol) and dimethyl-
formamide (2.2 mL) was stirred overnight at 40 °C. After cooling to
room temp., ethyl acetate (20 mL) was added and the organic layer
was washed with water (twice, 10 mL) and brine. Drying (Na2SO4),
concentration and column chromatography (EtOAc, hexanes, 2:8)
afforded the monomer as a clear colorless oil, which slowly solidi-
fied (607 mg, 88 %). Rf = 0.18 (EtOAc/hexanes, 2:8). 1H NMR
(CDCl3): δ = 1.26–1.44 [m, 27 H, OCH2CH2(CH2)9, C(CH3)3], 1.77
(m, 2 H, OCH2CH2CH2), 3.10 [m, 2 H, NHCH2(CH2)11], 3.61 (m,
2
H, NHCH2CH2O), 3.90 (s, 3 H, OCH3), 3.96 [t, 2 H,
OCH2(CH2)11], 4.06 (t, 2 H, OCH2CH2NH), 4.51 [br. s, 1 H,
NH(CH2)12], 5.12 [s, 2 H, ArCH2 (Cbz)], 5.23 [br. s, 1 H,
NH(CH2)2O], 6.62 (t, J = 2.2 Hz, 1 H, Ph C4-H), 7.17 (m, 2 H, Ph
C2,6-H), 7.28–7.37 [m, 5 H, C6H5 (Cbz)] ppm. 13C NMR: δ = 25.7,
26.5, 28.2, 28.9, 29.0, 29.1, 29.3, 29.8 [OCH2(CH2)10], 28.2
[C(CH3)3], 40.3 (NHCH2), 51.8 (OCH3), 66.5, 66.9 [ArCH2 (Cbz),
OCH2CH2NH], 68.0 [OCH2(CH2)11], 78.5 [C(CH3)3], 106.3, 107.3,
108.0 (Ph C2,4,6), 127.8, 128.2 [Ar C2–6 (Cbz)], 131.7 (Ph C1), 136.3
[Ar C1 (Cbz)], 155.8, 156.2 [C=O (Boc, Cbz)], 159.3, 160.0 (Ph
C3,5), 166.4 (CO2Me) ppm.
1
1:9). M.p. 75 °C. H NMR (CDCl3/CD3OD): δ = 1.27 [m, 64 H, 4
× NHCH2CH2(CH2)8], 1.63 [m, 8 H, 4 × NHCH2CH2(CH2)10],
1.73 [m, 8 H, 4 × OCH2CH2(CH2)10], 3.17 [t, 8 H, 4 ×
NHCH2(CH2)11], 3.57 (t, 8 H, 4 × ArNHCH2CH2O), 3.74 [m, 12
H, 6 × PhC(O)NHCH2CH2O], 3.85 (s, 3 H, OCH3), 3.91 [t, 8 H,
4 × OCH2(CH2)11], 4.09–4.16 (m, 20 H, 6 × OCH2CH2NHC=O, 4
× OCH2CH2NHAr), 6.54 (4 lines, 22 H, 8 × Ar C2,6-H, Ph C4Ј,4ЈЈ
-
H), 6.70 (br. s, 1 H, Ph C4-H), 6.91 (br. s, 8 H, Ph C2ЈЈ,6ЈЈ-H), 6.97
(br. s, 4 H, Ph C2Ј,6Ј-H), 7.13 (br. s, 2 H, Ph C2,6-H), 8.01 (2d, 16
H, 8 × Ar C3,5-H) ppm. 13C NMR (DMSO): δ = 25.5, 26.5, 28.3,
28.6, 28.8, 29.0 [NHCH2(CH2)10], 38.9 [PhC(O)NHCH2] 41.9, 42.3 Monomer 19: To a solution of monomer 18 (277 mg, 0.40 mmol)
(ArNHCH2), 52.1 (OCH3), 66.4, 67.7 [OCH2CH2NHAr, in ethanol (15 mL) was added chloroform (0.3 mL) and 10 % Pd/
OCH2CH2NHC=O, OCH2(CH2)11], 104.0, 105.7, 106.1, 107.7 (Ph C (app. 10 mg). The mixture was shaken under hydrogen (3 bar) in
C2,4,6,2Ј,4Ј,6Ј,2ЈЈ,4ЈЈ,6ЈЈ), 110.5, 110.8 (Ar C2,6), 126.1, 126.2 (Ar C3,5),
a Parr apparatus overnight. After the catalyst was removed by fil-
Eur. J. Org. Chem. 2005, 487–495
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
493

A. J. Brouwer, R. M. J Liskamp
FULL PAPER
tration through Hyflo, the mixture was concentrated and coevapo-
rated with chloroform. The hydrochloride salt was obtained as a
yellow oil (206 mg, 97 %). The hydrochloride salt (187 mg,
0.315 mmol) was used in a substitution reaction with 1-fluoro-4-
nitrobenzene (41.1 µL, 0.387 mmol), following the procedure de-
scribed in the synthesis of 11. Column chromatography (DCM)
afforded the product as a yellow oil (160 mg, 82 %). Rf = 0.88
[C(CH3)3], 39.5, 39.9 [CH2NHBoc, CH2NHC(O)Ph], 42.4
(ArNHCH2), 43.2 [NHCH2(CH2)11], 52.1 (OCH3), 66.2
(OCH2CH2NHAr),
66.9
[OCH2CH2NHC(O)Ph],
67.3
(OCH2CH2NHBoc), 68.3 [OCH2(CH2)11], 79.5 [C(CH3)3], 104.6,
105.1, 106.2, 108.0 (Ph C2,4,6,2Ј,4Ј,6Ј), 110.7, 111.1 (Ar C2,6), 126.2,
126.3 (Ar C3,5), 131.9 (Ph C1), 136.4 (Ph C1Ј), 137.3, 137.9 (Ar C1),
153.1, 153.6 (Ar C4), 155.8 (C=O (Boc)], 159.4, 159.5, 160.4 (Ph
(MeOH/DCM, 1:9). 1H NMR (CDCl3): δ = 1.23–1.40 [m, 27 H, C3,5,3Ј,5Ј), 166.4 (CO2Me), 167.4 [NHC(O)Ph] ppm. MS (FAB);
OCH2CH2(CH2)10, C(CH3)3], 1.73 [m, 2 H, OCH2CH2(CH2)10],
3.04 [m, 2 H, NHCH2(CH2)11], 3.58 (m, 2 H, NHCH2CH2O), 3.85
(s, 3 H, OCH3), 3.91 [t, J = 6.5 Hz, 2 H, OCH2(CH2)11], 4.16 (m,
2 H, OCH2CH2NH), 4.62 [br. s, 1 H, NH(CH2)12], 5.27 [bt, 1 H,
NH(CH)2O], 6.59 (m, 3 H, Ar C3,5-H, Ph C4-H), 7.11, 7.15 (2s, 2
H, Ph C2,6-H), 8.02 (d, 2 H, Ar C2,6-H, J = 9.2 Hz) ppm. 13C
NMR: δ = 25.8, 26.6, 29.0, 29.1, 29.2, 29.4, 29.9 [OCH2(CH2)10],
28.3 [C(CH3)3], 40.5 [NHCH2(CH2)11], 42.4 (NHCH2CH2O), 52.1
(OCH3), 66.2 (OCH2CH2NH), 68.3 [OCH2(CH2)11], 78.8
[C(CH3)3], 106.5, 107.3, 108.3 (Ph C2,4,6), 111.1 (Ar C2), 126.2 (Ar
C3), 131.9 (Ph C1), 138.1 (Ar C1), 153.1 (Ar C4), 155.9 [C=O (Boc)],
159.2, 160.2 (Ph C3,5), 166.6 (CO2Me) ppm.
m/z [M + H]+ = 959.5.
Dendrimer 22: To a solution of 21 (329 mg, 0.347 mmol) in dichlo-
romethane (4 mL) was added diethylether (4 mL), saturated with
HCl. The mixture was concentrated in vacuo and dried with KOH
overnight, giving the hydrochloride salt as a yellow foam (301 mg,
98 %). Monomer 19 (160 mg, 0.260 mmol) was saponified usingthe
procedure described in the synthesis of 14 affording a yellow solid
(152 mg, 97 %). To this carboxylic acid was added the hydrochlo-
ride salt (223 mg, 0.253 mmol), BOP (122 mg, 0.277 mmol), dichlo-
romethane (2.5 mL) and DiPEA (143 µL, 0.821 mmol). After stir-
ring the mixture for 75 min at room temp., the solvent was
evaporated and ethyl acetate was added. The organic layer was
washed with 1 m KHSO4 (twice), 1 m NaOH (twice) and brine,
dried (Na2SO4) and concentrated. Column chromatography
(MeOH/DCM, 2:98) afforded the dendrimer as a yellow foam
(275 mg, 76 %). Rf = 0.68 (MeOH/DCM, 1:9). M.p. 50 °C. 1H
Monomer 20: A mixture of 5 (1.09 g, 3.50 mmol), 17 (1.17 g,
4.55 mmol), K2CO3 (1.09 g, 7.88 mmol) and dimethylformamide
(10 mL) was stirred overnight at 40 °C. After cooling to room
temp., the mixture was filtered over Hyflo and concentrated in
vacuo. Ethyl acetate was added, and the organic layer was washed
with water (twice) and brine. Drying and concentration in vacuo,
followed by column chromatography (EtOAc/hexanes, 3:7) afforded
NMR (CDCl3):
BocNHCH2(CH2)9, ArNHCH2CH2(CH2)8], 1.61 [m,
δ
=
1.24–1.43 [m, 43 H, C(CH3)3,
H,
2
ArNHCH2CH2(CH2)10], 1.69 [m, 4 H, 2 × OCH2CH2(CH2)10], 3.07
[m, 2 H, BocNHCH2(CH2)12], 3.16 [m, 2 H, ArNHCH2(CH2)11], 3.54
the monomer as a clear colorless oil (1.53 g, 89 %). Rf = 0.18
1
(EtOAc/hexanes, 3:7). M.p. 58 °C. H NMR (CDCl3): δ = 1.45 [s, (m, 4 H, 2 × ArNHCH2CH2O), 3.77 [m, 4 H, 2 × PhC(O)NHCH2],
9 H, C(CH3)3], 3.52, 3.60 (2 m, 4 H, 2 × NHCH2), 3.89 (s, 3 H, 3.81 (s, 3 H, OCH3), 3.86 [m, 4 H, 2 × OCH2(CH2)11], 4.03 (m, 4
OCH3), 4.01 (m, 4 H, 2 × OCH2), 5.02 (br. s, 1 H, NHBoc), 5.11
H, 2 × OCH2CH2NHC=O), 4.11 (m, 4 H, 2 × OCH2CH2NHAr),
(s, 2 H, ArCH2), 5.29 (br. s, 1 H, NHCbz), 6.61 (s, 1 H, Ph C4-H), 4.65 (br. s, 1 H, NHBoc), 5.02 [m, 1 H, ArNH(CH2)12], 5.45 [m, 2
7.16 (s, 2 H, Ph C2,6-H), 7.34 (m, 5 H, C6H5) ppm. 13C NMR H, 2 × ArNH(CH2)2O], 6.51 (m, 9 H, Ph C4-H, 2 × Ph C4Ј-H, 3
(CDCl3): δ = 28.3 [C(CH3)3], 39.9, 40.4 (NHCH2), 52.2 (OCH3),
66.8, 67.2, 67.5 (ArCH2, OCH2), 79.5 [C(CH3)3], 106.5, 108.0, H), 7.19 [br. s, 2 H, 2 × NHC(O)Ph], 7.98 (m, 6 H, 3 × Ar C3,5
108.2 (Ph C2,4,6), 128.0, 128.1, 128.5 (Ar C2–6), 132.1 (Ph C1), 136.3
× Ar C2,6-H), 6.93, 6.98, 7.03 (3s, 6 H, Ph C2,6-H, 2 × Ph C2Ј,6Ј
-
-
H) ppm. 13C NMR (CDCl3): δ = 25.8, 26.6, 26.8, 28.8, 29.0, 29.1,
(Ar C1), 155.8, 156.3 [C=O (Boc, Cbz)], 159.5, 159.6 (Ph C3,5), 29.2, 29.3, 29.4 [OCH2(CH2)10], 28.3 [C(CH3)3], 39.5 (NHCH2)
166.5 (CO2Me) ppm. MS (ESI): m/z = 389.3 [M – Boc + H]+, 511.4
[M + Na]+ . C25H32N2O8 (488.53): calcd. C 61.46, H 6.60, N 5.73;
found C 61.48, H 6.64, N 5.71.
40.5
(BocNЈHCH2),
42.4
(ArNЈHCH2CH2O),
43.2
[ArNЈHCH2(CH2)11], 52.1 (OCH3), 66.2 (OCЈH2CH2NH), 66.7
(OCH2CH2NH), 68.2 [OCЈH2(CH2)11], 78.9 [C(CH3)3], 104.6,
105.1, 106.1, 106.2, 108.1 (Ph C2,4,6,2Ј,4Ј,6Ј), 110.7, 111.0 (Ar C2,6),
126.2, 126.3 (Ar C3,5), 131.8 (Ph C1), 136.2, 137.1, 137.7, 136.3 (Ph
C1Ј, Ar C1), 153.3, 153.7 (Ar C4), 155.9 [C=O (Boc)], 159.3, 159.4,
160.3 (Ph C3,5,3Ј,5Ј), 166.4, 167.5 (CO2Me, NHC=O) ppm. MS
(FAB): m/z = 1443.1 [M + H]+. C77H103N9O18 (1442.69): calcd. C
64.10, H 7.20, N 8.74; found C 63.92, H 7.18, N 8.70.
Half Coupled Dendrimer 21: Monomer 20 was Cbz-deprotected fol-
lowing the procedure described in the synthesis of 19, affording
the hydrochloride salt in a quantitative yield. To a mixture of the
hydrochloride salt (0.45 mmol), 13 (280 mg, 0.45 mmol), BOP
(218 mg, 0.495 mmol) and dry dichloromethane, was added DiPEA
(255 µL, 1.46 mmol). The mixture was stirred at room temp. for 1
h. After concentration, the residue was dissolved in ethyl acetate
and washed with 1 m KHSO4 (twice), 1 m NaOH (twice) and brine.
The organic layer was dried (Na2SO4) and the solvents evaporated
in vacuo. Column chromatography (MeOH/DCM, 2:98) afforded
the product as a yellow foam (333 mg, 78 %). Rf = 0.74 (MeOH/
Dendrimer-to-Dendrimer System 23: Dendrimer 22 (161 mg,
0.113 mmol) was saponified using the procedure described in the
synthesis of 14 affording the acid as a yellow foam (156 mg, 98 %).
To a solution of dendrimer 22 (54.9 mg, 21.7 µmol) was added
dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). After
stirring at room temp. for 15 min, the mixture was concentrated
DCM, 1:9). 1H NMR (CDCl3):
δ = 1.21–1.42 [m, 25 H,
OCH2CH2(CH2)8, C(CH3)3], 1.61 [m, 2 H, NHCH2CH2(CH2)10], and co-evaporated with chloroform (three times). The acid
1.71 [m, 2 H, OCH2CH2(CH2)10], 3.16 [m, 2 H, ArNHCH2- (30.7 mg, 21.5 µmol), BOP (10.5 mg, 23.9 µmol), dry acetonitrile
(CH2)11], 3.47 (m, 2 H, BocNHCH2), 3.57 (m, 2 H, ArNHCH2- (0.5 mL) and DiPEA (12 µL, 70 µmol) were added, and the mix-
CH2O), 3.80 [m, 2 H, PhC(O)NHCH2], 3.85 (s, 3 H, OCH3), 3.89
ture was refluxed for 3 h. The solvent was evaporated and dichloro-
[m, 2 H, OCH2(CH2)11], 3.95 (m, 2 H, OCH2CH2NHBoc), 4.13 methane (20 mL) was added, after which the product slowly solidi-
[m, 4 H, OCH2CH2NHAr, OCH2CH2NHC(O)Ph], 4.87 [bt, 1 H, fied. Filtration followed by column chromatography (MeOH/
ArNH(CH2)12], 5.10 (br. s,
1
H, NHBoc), 5.28 [m,
1
H, DCM, 4:96) afforded dendrimer-to-dendrimer system 23 as a yel-
low foam (37 mg, 62 %). Rf = 0.32 (MeOH/DCM, 5:95). M.p.
64 °C. 1H NMR (CDCl3/CD3OD): δ = 1.21–1.43 [m, 75 H,
ArNH(CH2)2O], 6.47 (m, 2 H, Ph C4,4Ј-H), 6.54 (m, 4 H, 2 × Ar
C2,6-H), 6.93 [m, 3 H, Ph C2Ј,6Ј-H, NHC(O)Ph], 7.10 (m, 2 H, Ph
C2,6-H), 8.00 (m, 4 H, 2 × Ar C3,5-H) ppm. 13C NMR (CDCl3): δ C(CH3)3, BocNHCH2(CH2)9, NHCH2CH2(CH2)8], 1.57–1.71 [m,
= 25.8, 26.8, 28.9, 29.0, 29.1, 29.2, 29.3 [OCH2(CH2)10], 28.3
494
14 H, 2 × ArNHCH2CH2(CH2)10, PhC(O)NHCH2CH2(CH2)10,
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 487–495

Novel Dendrimeric Systems Containing NLO Ligands
FULL PAPER
4 × OCH2CH2(CH2)10], 3.06 (m, 2 H, BocNHCH2), 3.16 [m, 4 H, ppm. The signals of C(CH3)3 and C=O (Boc) were not visible in
2 × ArNHCH2(CH2)11], 3.35 [m, 2 H, PhC(O)NHCH2(CH2)11], the 13C NMR. MS (ESI): m/z = 1993.7 [M – Boc + Na + H]2+
3.55 (m, 8 H, 4 × ArNHCH2CH2O), 3.74 [m, 8 H, 4 × PhC(O) 2054.7 [M + 2Na]2+, 2732.2 [2M + 3Na]3+, 4086.8 [M + Na]+.
,
NHCH2CH2O], 3.85 (s, 3 H, OCH3), 3.89 [m, 8 H, 4 × OCH2-
(CH2)11], 4.02 [m, 8 H, 4 × OCH2CH2NHC(O)Ph], 4.12 (m, 8 H,
4 × OCH2CH2NHAr), 4.70 (br. s, 1 H, NHBoc), 5.03 [br. s, 2 H,
2 × ArNH(CH2)12O], 5.57 [br. s, 4 H, 4 × ArNH(CH2)2O], 6.39–
6.56 (m, 18 H, 6 × Ar C2,6-H, Ph C4,4ЈЈ-H, 2 × Ph C4Ј,4ЈЈЈ-H), 6.85–
7.05 (m, 12 H, Ph C2,6,2ЈЈ,6ЈЈ-H, 2 × Ph C2Ј,6Ј,2ЈЈЈ,6ЈЈЈ-H), 7.36 [br. s,
5 H, 5 × NHC(O)Ph], 8.00 (m, 12 H, 6 × Ar C3,5-H) ppm. 13C
NMR (CDCl3/CD3OD): δ = 25.6, 25.7, 26.2, 26.7, 28.7, 28.9, 29.0
(2 ×), 29.2 (2 ×), 29.3, 29.5, 29.7 [OCH2(CH2)10], 28.1 [C(CH3)3],
39.2, 39.3 [PhC(O)NHCH2], 40.3 (BocNHCH2), 42.2 (ArNHCH2-
CH2O), 43.0 [ArNHCH2(CH2)11], 52.1 (OCH3), 66.3, 66.5, 66.7
(OCH2CH2NH), 68.3 [OCH2(CH2)11], 104.5, 104.7, 105.2, 106.2,
108.2 (Ph C2,4,6), 110.6, 110.9 (Ar C2,6), 126.2, 126.3 (Ar C3,5),
131.8 (Ph C1), 136.1, 136.6, 136.9, 137.5 (Ar C1, Ph C1,1Ј,1ЈЈ,1ЈЈЈ),
153.5, 153.6, 153.9 (Ar C4), 159,6, 160.3 (Ph C3,5), 166.7 (CO2Me),
167.5, 168.0 [PhC(O)NH] ppm. The signals of C(CH3)3 and C=O
(Boc) were not visible in the 13C NMR. MS (FAB): m/z = 2651.3
[M – Boc]+. C148H194N18O33 (2753.23): calcd. C 64.56, H 7.10, N
9.16; found C 64.70, H 7.18, N 9.19.
C219H285N27O48 (4063.76): calcd. C 64.73, H 7.07, N 9.31; found
C 64.80, H 6.97, N 9.12.
Acknowledgments
These investigations were supported in part by the Council for
Chemical Sciences of the Netherlands Organization for Scientific
Research (CW-NWO) with financial aid from the Netherlands
Technology foundation. We thank Mr. C. Versluis from the Depart-
ment of Biomolecular Mass Spectrometry for recording some of
the mass spectra.
[1] For recent reviews see, for example: G. R. Newkome, C. N.
Moorefield, F. Vögtle, Dendrimers and Dendrons: Concepts,
Syntheses, Applications, Wiley, New York, 2001.
[2] a) I. Vrasidas, J. Kemmink, R. M. J. Liskamp, R. J. Pieters,
Org. Lett. 2002, 4, 1807–1808; b) I. Vrasidas, S. Andre, P. Va-
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J. Gabius, R. J. Pieters, Org. Biomol. Chem. 2003, 1, 803–810;
c) R. Autar, A. S. Khan, M. Schad, J. Hacker, R. M. J. Lis-
kamp, R. J. Pieters, ChemBioChem2003, 4, 1317–1325; d) D.
Arosio, I. Vrasidas, P. Valentini, R. M. J. Liskamp, R. J. Pieters,
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R. M. J. Liskamp, Tetrahedron Lett.1997, 38, 631–634; b)
S. J. E. Mulders, A. J. Brouwer, R. M. J. Liskamp, Tetrahedron
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R. M. J. Liskamp, Eur. J. Org. Chem.2001, 1903–1915.
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R. M. J. Liskamp, J. Chem. Soc. Perkin Trans. 21998, 7, 1535–
1538.
Dendrimer-to-Dendrimer System 24: To a solution of dendrimer 23
(13.0 mg, 4.72 µmol) was added dichloromethane (0.5 mL) and tri-
fluoroacetic acid (0.5 mL). After 30 min stirring at room temp., the
mixture was concentrated and coevaporated with chloroform (three
times). Saponified 22 (6.6 mg, 4.62 µmol), BOP (2.3 mg, 5.22
µmol), dry acetonitrile (0.25 mL) and a DiPEA solution in dichlo-
romethane (10 % v/v, 48 µL, 27.7 µmol) were added. The mixture
was refluxed for 3 h, followed by evaporation of the solvent. Purifi-
cation by column chromatography (MeOH/DCM, 3:97) and pre-
parative TLC (MeOH/DCM, 5:95), afforded dendrimer-to-den-
drimer system 24 as a yellow film (5.7 mg, 30 %). Rf = 0.30
(MeOH/DCM, 5:95). 1H NMR (CDCl3/CD3OD): δ = 1.21–1.56
[m, 107 H, C(CH3)3, BocNHCH2(CH2)9, 5 × NHCH2CH2-
(CH2)8], 1.59–1.72 [m, 22 H, 3 × ArNHCH2CH2(CH2)10, 2 ×
[5] For recent examples of applications of dendrimers in materials
see, for example: C. A. Schalley, F. Vögtle, in: Dendrimers V:
Functional and Hyperbranched Building Blooks, Photophysical
Properties, Applications in Materials and Life Sciences,
Springer-Verlag, Berlin, Heidelberg, New York, 2003.
PhC(O)NHCH2CH2(CH2)10, 6 × OCH2CH2(CH2)10], 3.07 (m, 2 H, [6] For recent examples of NLO containing dendrimers see, for
example: a) A. M. McDonagh, M. G. Humphrey, M. Samoc,
B. Luther-Davies, Organometallics1999, 18, 5195–5197; b) O.
Varnavski, A. Leanov, L. Liu, J. Takacs, T. Goodson, III, J.
Phys. Chem. B2000, 104, 179–188; c) H. Ma, A. K.-Y. Jen,
Adv. Mater. 2001, 13, 1201–1205; d) H. Ma, B. Chen, T. Sassa,
L. R. Dalton, A. K.-Y. Jen, J. Am. Chem. Soc.2001, 123, 986–
987; e) J. Wang, M. Lu, Y. Pan, Z. Peng, J. Org. Chem.2002,
67, 7781–7786; f) H. Ma, S. Liu, J. Luo, S. Suresh, L. Liu, S. H.
Kang, M. Haller, T. Sassa, L. R. Dalton, A. K.-Y. Jen, Adv.
Funct. Mater. 2002, 12, 565–574; g) J. L. Casson, H.-L. Wang,
J. B. Roberts, A. N. Parikh, J. M. Robinson, M. S. Johal, J.
Phys. Chem. B2002, 106, 1697–1702; h) Y. V. Pereverzev, O. V.
Prezhdo, L. R. Dalton, Chem. Phys. Lett.2003, 373, 207–212;
i) J. Luo, M. Haller, H. Ma, S. Liu, T.-D. Kim, Y. Tian, B.
Chen, S.-H. Jang, L. R. Dalton, A. K.-Y. Jen, J. Phys. Chem.
B 2004, 108, 8523–8530.
BocNHCH2), 3.15 [m, 6 H, 3 × ArNHCH2(CH2)11], 3.35 [m, 4 H,
PhC(O)NHCH2(CH2)11], 3.57 (m, 12 H, 6 × ArNHCH2CH2O),
3.70 [m, 12 H, 6 × PhC(O)NHCH2CH2O], 3.86 (s, 3 H, OCH3),
3.89 [m, 12 H,
6 × OCH2(CH2)11], 4.02 [m, 12 H, 6 ×
OCH2CH2NHC(O)Ph], 4.13 (m, 12 H, 6 × OCH2CH2NHAr), 4.76
(br. s, 1 H, NHBoc), 5.12 [br. s, 3 H, 3 × ArNH(CH2)12O], 5.67
[br. s, 6 H, 6 × ArNH(CH2)2O], 6.37–6.56 (m, 27 H, 9 × Ar C2,6
-
H, Ph C4,4ЈЈ,4ЈЈЈЈ-H, 2 × Ph C4Ј,4ЈЈЈ,4ЈЈЈЈЈ-H), 6.83–7.07 (m, 18 H, Ph
C2,6,2ЈЈ,6ЈЈ,2ЈЈЈЈ,6ЈЈЈЈ-H, 2 × Ph C2Ј,6Ј,2ЈЈЈ,6ЈЈЈ,2ЈЈЈЈЈ,6ЈЈЈЈЈ-H), 7.56 (br. m, 8
H, 8 × NHC(O]Ph), 8.01 (m, 18 H, 9 × Ar C3,5-H) ppm. 13C NMR
(CDCl3/CD3OD): δ = 25.8, 26.8, 28.2, 28.8, 29.0, 29.1, 29.3, 29.4,
29.5 [OCH2(CH2)10, C(CH3)3], 39.3, 42.2, 43.0 [PhC(O)-
NHCH2, BocNHCH2, ArNHCH2, ArNHCH2(CH2)11], 52.2
(OCH3), 63.8, 66.1, 66.4, 68.2 [OCH2CH2NH, OCH2(CH2)11],
103.9, 104.6, 105.1, 105.7, 106.2, 108.0, 110.6, 110.9 (Ph C2,6),
110.6, 110.9 (Ar C2,6), 126.3, 126.4 (Ar C3,5), 131.9 (Ph C1), 136.0,
136.5, 137.4 (Ar C1, Ph C1–1ЈЈЈЈЈ), 153.5, 153.8 (Ar C4), 159.4,
159.5.3, 160.2 (Ph C3,5), 166.7 (CO2Me), 167.5, 168.0 [PhC(O)NH]
[7] G. I. Tesser, I. C. Balvert-Geers, Int. J. Peptide Protein Res.
1975, 7, 295–305: “Tesser’s base”: dioxane/methanol/2 n or 4 n
NaOH (14:5:1).
Received August 27, 2004
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