Synthesis and characterisation of peripherally functionalised dendritic molecules

Article abstract of DOI:10.1039/b609500c

A number of peripherally functionalised dendritic molecules were synthesised in almost quantitative yield by a synthetic method involving the reaction between amines and isocyanates. The peripheral functional groups were incorporated by preparing a number

Full text of DOI:10.1039/b609500c

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PAPER
www.rsc.org/njc | New Journal of Chemistry
Synthesis and characterisation of peripherally functionalised dendritic
molecules
Sarah J. Atkinson, Vicky-June Ellis, Sue E. Boyd and Christopher L. Brown*
Received (in Montpellier, France) 4th July 2006, Accepted 27th September 2006
First published as an Advance Article on the web 13th October 2006
DOI: 10.1039/b609500c
A number of peripherally functionalised dendritic molecules were synthesised in almost
quantitative yield by a synthetic method involving the reaction between amines and isocyanates.
The peripheral functional groups were incorporated by preparing a number of branched subunits,
based on tris(hydroxymethyl)aminomethane (TRIS), 1, possessing three nitro, methoxy, methyl or
maleimide terminal functionalities. Attachment of these branched units to the core molecules
4,40-methylenebis(phenyl isocyanate) 13 and 1,3,5-benzene triisocyanate 20 afforded the
corresponding dendritic molecules possessing 6 or 9 peripheral functional groups. Functional
group conversions on the dendritic molecules have been successfully carried out, including
hydrogenation of the terminal nitro to the corresponding amine and cleavage of the methoxy
ether to give the corresponding phenol.
cules via urea linkages, by utilising the facile reaction
Introduction
occurring between amines and isocyanates. Such a modular
A rising demand for well-defined, functional materials for
strategy provides ample opportunity for tailoring of the final
nano-scale applications has stimulated the development of
molecules for specific applications and properties.
synthetic procedures for the efficient assembly of dendritic
and polymeric species.1 Several synthetic approaches to these
Synthesis of branched dendrons with peripheral functionality
systems feature architectural control while still maintaining
flexibility in the incorporation of functional groups.2 How-
ever, many approaches to dendrimer syntheses, particularly in
later generations, require high monomer loading and involve
prolonged, repetitive, chromatographic separations, generat-
ing considerable waste.3 In an attempt to overcome this
problem a growing number of synthetic approaches are utilis-
ing facile coupling techniques for the assembly of macromo-
lecular dendritic and polymeric structures.4 Recently, several
urea-based syntheses have been reported for the divergent
growth of dendrimers5–7 and other macro-molecular struc-
tures.8 Here we report a highly efficient, facile approach for the
modular synthesis of a diverse range of peripherally functio-
nalised structures that can serve as scaffolds for the assembly
of more complex macromolecular structures for use in nano-
technology, biological and materials sciences. The syntheses
utilise the well-documented reaction between an isocyanate
and an amine and afford peripherally functionalised nanopar-
ticles in excellent yields and purity.
The synthesis of the branched dendrons, bearing three term-
inal residues and based on the inexpensive starting material
tris(hydroxymethyl)aminomethane (TRIS) 1, involved the
coupling of 3.3 equivalents of an appropriately para-substi-
tuted benzoic acid chloride with Boc protected TRIS 2 in
dichloromethane (DCM) in the presence of triethylamine
(Scheme 1).
Results and discussion
Synthetic strategy
The synthetic strategy utilised in this body of work was based
on the preparation of a number of branched synthetic building
blocks possessing differing terminal functionality. These den-
drons were then attached to bi- and tri-functional core mole-
Chemical Biology Program, Eskitis Institute, Griffith University,
Nathan, Brisbane, Australia. E-mail: c.l.brown@griffith.edu.au;
Fax: +61-7-37357656; Tel: +61-7-37357293
Scheme 1 Synthesis of the branched dendrons.
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The p-nitro, p-methoxy and p-methyl benzoyl chloride
starting materials were obtained commercially, whilst
N-(4-carboxyphenyl)maleimide was synthesised according to
literature procedures.9 Conversion of N-(4-carboxyphenyl)-
maleimide to the required acid chloride was carried out
immediately prior to use via standard procedures using thionyl
chloride. Initial synthesis of the maleimide 3-mer dendron (N-
(tert-butyloxycarbonyl)-1,1,1-tris(4-maleimidobenzoyloxy-methyl)
methylamine) 6 resulted in low yields due to unwanted poly-
merisation. Subsequent procedures utilising tert-butylcatechol
to suppress polymerisation9 resulted in higher yields being
obtained. The Boc protected dendrons 3–6 were synthesised in
yields ranging from 41–92%. Deprotection of the Boc pro-
tected dendrons 3 and 4 in DCM with trifluoroacetic acid
(TFA), followed by the addition of 1 M sodium carbonate
afforded the TFA salts 7 and 9, respectively. The correspond-
ing free base amines 8 and 10 were obtained on further
treatment of the TFA salts with sodium carbonate. Deprotec-
tion of the Boc protected dendrons 5 and 6 afforded the
free amines 11 and 12 directly after treatment with sodium
carbonate.
species, suggesting incomplete reactions, were not observed in
the crude products isolated in all cases. Formation of the urea
linkages were confirmed through two-dimensional NMR ex-
periments and the corresponding cross peaks can be clearly
identified in the gHMBC spectrum (Fig. 2).
1,3,5-Benzene triisocyanate 20 was selected as the tri-func-
tional core unit for the synthesis of the more radially distrib-
uted 9-mer systems,. This material was prepared, according to
a literature procedure,7 from the corresponding 1,3,5-benze-
netricarbonyl triazide precursor 19, via a Curtius rearrange-
ment. Once prepared the acylazide precursor 19 was stored at
ꢁ20 1C until required, as this compound is reported to be
explosive under heat or pressure in the solid state.8 The
synthetic methodology for the assembly of the 9-mer systems
is shown in Scheme 3.
In most cases the products precipitated from the reaction
1
mixture after 18 h and were isolated simply by filtration. H
NMR analysis of the reaction products for the formation of
the nitro 6-mer 14 (Scheme 2) showed the formation of
spectroscopically pure product in a 75% yield. However, the
use of the trifunctional core 20 to assemble the analogous
9-mer nitro species 21 resulted in poor yields. Further inves-
tigation found that the application of gentle heat to the
reaction afforded required compound 21 in a 92% yield
(Scheme 3). Consequently, subsequent reactions to construct
the 6-mer and 9-mer species were carried out in refluxing
DCM. Formation of the methoxy 15 and maleimido 16
functionalised 6-mers recorded yields of 74 and 94% (Scheme
2), whilst the construction of the methoxy 22, methyl 23 and
maleimide 24 terminated 9-mers achieved yields of 96, 97, and
99%, respectively (Scheme 3). Solubility of both the 6-mer
and 9-mer species varies greatly with varying external func-
tionality. In all cases the methoxy and maleimido functiona-
lised molecules were soluble in dichloromethane and were
isolated via solvent removal at reduced pressure.
Synthesis of functionalised branched molecules containing 6- and
9-peripheral functionalities
The modular strategy devised for the synthesis of branched
molecules containing 6- and 9-peripheral functionalities pro-
vides for flexibility in the level of complexity available for
elaboration, as well as increasing the variety of peripheral
functional groups that could be incorporated. Initial investi-
gations were carried out on the commercially available
bi-functional 4,40-methylenebis(phenyl isocyanate) 13 as the
core unit. The synthetic methodology for the assembly of these
linear 6-mer systems is shown in Scheme 2.
The success of this system can be best illustrated through the
resultant NMR spectra of the ‘crude’ 6-nitro species as seen in
Fig. 1. The symmetry of the fully functionalised dendritic
system is evidenced in the NMR spectrum. Less symmetrical
Conversion of the peripheral nitro functionalised species 14
and 21 to the corresponding amines occurred smoothly via
hydrogenation using 5% Pd/C under elevated temperatures
and pressure (DMF, 55 1C, 600 psi) and afforded yields of the
polyamine 6-mer 17 in 62% yield and the 9-mer 25 in 60%
yield, respectively. Similarly, conversion of the methoxy pro-
tected 9-mer 22, to the phenolic compound 26 (AlBr3,
dodecane thiol, DCM) afforded the 9-mer polyphenol 26 in
87% yield.
Conclusions
We have demonstrated the facile assembly of highly mono-
disperse branched molecules possessing a range of peripheral
functionalities, based upon the high yielding coupling reaction
occurring between amines and isocyanates. The uniform at-
tachment of the dendrons to the bi- and tri-functionalised
cores is highly efficient and yields compounds of high purity
due to the quantitative reaction between the amines on the
branched dendrons and the isocyanates present on the core
molecules. Our investigations are continuing into the applica-
tion of these molecules as a basis for the assembly of more
complex macromolecular structures for applications in biolo-
gical and materials science.
Scheme 2 Synthesis of the 6-mer macromolecules.
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Fig. 1 1H NMR spectrum (400 MHz, 298 K, CD3COCD3–CD3SOCD3) of the crude 6-mer, 14.
Fig. 2 Expansion of the 1H/13C gHMBC spectrum of the 6-mer, 14 (400 MHz, 298 K, CD3COCD3–CD3SOCD3). Basic 1H and 13C{1H} spectra
are provided as axes references. Crosspeaks correlating the NH protons and the carbon of the central carbonyl of the urea linkage are highlighted.
light (254 nm) or in an iodine vapour tank. Chromatographic
Experimental
separations were carried out by column chromatography with
General methods and materials
Merck silica gel 60 A (230–400 mesh) as the stationary phase.
Anhydrous solvents were prepared according to literature
methods.10 Most reagents and starting materials were ob-
tained from commercial sources (Sigma-Aldrich) and used
without further purification. 4-Maleimidobenzoic acid9 and
1,3,5-benzenetricarbonyl triazide7 19 were prepared according
to published procedures. All reactions were performed in
flame-dried or oven-dried glassware under an inert atmosphere
of nitrogen. In all cases the isocyanate was prepared immedi-
ately prior to coupling with the appropriate amine. Analytical
TLC was carried out on Merck aluminium TLC plates coated
with silica gel 60 F254 (0.2 mm) and visualised by ultraviolet
NMR spectra were recorded on a Varian Unity INOVA
spectrometer. 1H (400 MHz) and 13C (100 MHz) chemical
shifts were referenced to the residual solvent peaks. gCOSY,
gHSQC and gHMBC spectra were acquired using the stan-
dard sequences contained in the VNMR6.1C software pack-
age. FTIR spectra were recorded in the range of 4000–
400 cmꢁ1 on a Thermo Nicolet-Nexus FTIR spectrometer.
Melting points were measured using the capillary method on a
GallenKamp Variable Temperature Apparatus and are un-
corrected. Mass spectra were recorded on a Fisons VG-Plat-
form II spectrometer, using positive and negative mode
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Scheme 3 Synthesis of the 9-mer branched molecules.
electrospray as the ionisation technique and Mass Lynx Ver-
sion I (IBM) software to acquire and process ESMS data.
Lithium was added to ESMS scans as LiBr. HRMS were
carried out by the Mass Spectrometry Facility, Griffith Uni-
versity on a Bruker Daltonics Apex III 4.7e Fourier Trans-
form Mass Spectrometer, fitted with an Apollo API source
and are within 2.5 ppm. Elemental analyses were carried out
by the Microanalytical Service, Department of Chemistry at
the University of Queensland, Brisbane.
(5.0 g, 23 mmol) and Et3N (11 ml, 79 mmol) in dry dichlor-
omethane (100 ml). The reaction was gently refluxed for 20
hours, then cooled to room temperature and filtered to remove
the precipitated triethylamine hydrochloride. The organic
solution was washed with saturated aqueous NaHCO3 (3 ꢂ
150 ml) and saturated aqueous NaCl (5 ꢂ 150 ml), dried
(MgSO4), filtered and evaporated under reduced pressure. The
crude product was purified by column chromatography (4%
ethyl acetate–dichloromethane) affording an ivory colored
solid (13.2 g, 87% yield); mp 147.5–149 1C. ESMS (+ve)
691 (MNa+, 65%), 675 (MLi+, 30%). IR(KBr, pellet, cmꢁ1
)
Synthesis
1
3391 m, 1725 s, 1526 s, 1349 m, 1276 s. H NMR (400 MHz,
DMSO-d6) d 8.29 (m (AA0), 6H, Ar–H), 8.18 (m (BB0), 6H,
Ar–H), 7.51 (br. s, 1H, NH), 4.81 (s, 6H, CH2), 1.34 (s, 9H,
CH3). 13C NMR (100 MHz, DMSO-d6) d 163.84 (CO2R),
154.74 (NH–CQO), 150.30 (ArC–NO2), 134.68 (ArC–CO2H),
130.74 (ArC–H), 123.76 (ArC–H), 78.79 (Cq–CH3), 63.78
(CH2), 56.57 (Cq–CH2), 28.01 (C–CH3). Anal. calcd for
C30H28N4O14: C, 53.89; H, 4.22; N, 8.38. Found: C, 54.12;
H, 4.35; N, 8.23%.
N-(tert-Butyloxycarbonyl)-1,1,1-tris(hydroxymethyl)methy-
lamine 2. Tris(hydroxylmethyl)aminomethane (1) (11.7 g,
97 mmol) was added as a solid to a solution of di-tert-butyl
dicarbonate (21.0 g, 96 mmol) in THF (200 ml) under an
atmosphere of nitrogen. The reaction mixture was stirred at
room temperature for 4 days. The resulting precipitate was
filtered off and washed thoroughly with cold THF then dried
under high vacuum to give a white powder (15.1 g, 73% yield)
as a spectroscopically pure product; mp 144–146 1C (lit.,11
147 1C). ESMS (ꢁve) 220 (Mꢁ, 20%); ESMS (+ve) 222
1
(M+, 15%), 228 (MLi+, 95%). H NMR (DMSO-d6) d 5.76
N-(tert-Butyloxycarbonyl)-1,1,1-tris(4-methoxybenzoyloxy-
methyl)methylamine 4. This compound was prepared by
a procedure analogous to that used for the preparation of
3 using p-anisoyl chloride (12.7 g, 75 mmol) and 2 (5.0 g,
23 mmol). The crude product was purified by column chro-
matography (2% ethyl acetate–CH2Cl2) affording a white
foamy solid (13.0 g, 92% yield); mp 136 1C. ESMS (+ve)
630 (MLi+, 100%), 647 (MNa+, 100%). IR(KBr, pellet,
cmꢁ1) 3364 m, 2976 w, 1718 s, 1697 s, 1606 s, 1255 s. 1H
(br. s, 1H, NH), 4.49 (br. t, 3H, OH), 3.51 (d, 6H, CH2), 1.37
(s, 9H, CH3). 13C NMR12 (DMSO-d6) d 155.03 (CQO), 77.83
(Cq–CH3), 60.45 (CH2), 60.24 (Cq–CH2), 28.22 (CH3).
N-(tert-Butyloxycarbonyl)-1,1,1-tris(4-nitrobenzoyloxy-methyl)
methylamine 3. A solution of 4-nitrobenzoyl chloride (14.0 g,
74.6 mmol) dissolved in dichloromethane (30 ml) was added
dropwise, under an atmosphere of nitrogen, to a solution of 2
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NMR (400 MHz, DMSO-d6) d 7.91 (m (AA0), 6H, Ar–H),
7.34 (br. s, 1H, NH) 7.00 (m (XX0), 6H, Ar–H), 4.65 (s, 6H,
CH2), 3.82 (s, 9H, O–CH3), 1.34 (s, 9H, C–CH3). 13C NMR
(100 MHz, DMSO-d6) d 164.93 (CO2R), 163.24 (ArC–OCH3),
154.69 (NH–CQO), 131.37 (ArC–H), 121.53 (ArC–CO2R),
113.93 (ArC–H), 78.47 (Cq–CH3), 62.85 (CH2), 56.77
(Cq–CH2), 55.48 (O–CH3), 28.04 (C–CH3). Anal. calcd for
C33H37NO11: C, 63.55; H, 5.98; N, 2.25. Found: C, 63.64; H,
6.01; N, 2.21%.
1,1,1-Tris(4-nitrobenzoyloxymethyl)methylamine trifluoro-
acetic acid salt 7. N-(tert-Butyloxycarbonyl)-1,1,1-tris(4-nitro-
benzoyloxy-methyl)methylamine (3) (3.5 g, 5.3 mmol) was
dissolved in the minimum amount of dichloromethane then
trifluoroacetic acid (3 ml) was added and the solution was
refrigerated for 18 hours. The organic solution was poured
into 1 M aqueous Na2CO3 and the resulting white precipitate
was collected by filtration and dried (3.59 g, 99% yield); mp
158–159 1C. ESMS (ꢁve) 113 (CF3COOꢁ, 95%). ESMS (+ve)
569 (M+, 100%). IR(KBr, pellet, cmꢁ1) 1742 s, 1729 s, 1267 s.
1H NMR (400 MHz, DMSO-d6) d 9.32 (br. s, 3H, NH3+),
8.36 (m (AA0BB0), 12H, Ar–H), 4.81 (s, 6H, CH2). 13C NMR
(100 MHz, DMSO-d6) d 163.79 (CO2R), 150.55 (ArC–NO2),
134.16 (ArC–CO2R), 131.25 (ArC–H), 123.68 (ArC–H), 63.66
(CH2), 56.38 (Cq). Anal. calcd for C27H21F3N4O14 ꢃ H2O: C,
46.29; H, 3.31; N, 8.00. Found: C, 46.01; H, 2.95; N, 7.95%.
N-(tert-Butyloxycarbonyl)-1,1,1-tris(4-methylbenzoyloxy-
methyl)methylamine 5. This compound was prepared by a
procedure analogous to that used for the preparation of 3
using p-toluoyl chloride (11.7 g, 10.0 ml, 76 mmol) and 2
(5.0 g, 23 mmol). The crude product was purified by column
chromatography (gradient elution 50–65% dichlorometha-
ne–hexane) to yield a white solid (12.00 g, 20.8 mmol, 92%);
mp 129–131 1C. ESMS (+ve) 582 (MLi+, 100%), 598
(MNa+, 100%). IR(KBr, pellet, cmꢁ1) 3378 m, 2977 w,
1726 s, 1704 s, 1271 s. 1H NMR (400 MHz, DMSO-d6) d
7.85 (m (AA0), 6H, Ar–H), 7.38 (br. s, 1H, NH), 7.28 (m
(XX0), 6H, Ar–H), 4.67 (s, 6H, CH2), 2.36 (s, 9H, Ar–CH3),
1.33 (s, 9H, C–CH3). 13C NMR (100 MHz, DMSO-d6) d
165.25 (CO2R), 154.69 (NH–CQO), 143.78 (ArC–CH3),
129.29 (ArC–H), 129.20 (ArC–H), 126.61 (ArC–CO2R),
78.49 (Cq–CH3), 62.96 (CH2), 56.73 (Cq–CH2), 28.03
(C–CH3), 21.13 (ArC–CH3). Anal. calcd for C33H37NO8: C,
68.85; H, 6.48; N, 2.43. Found: C, 69.12; H, 6.46; N, 2.42%.
1,1,1-Tris(4-nitrobenzoyloxymethyl)methylamine 8. 7 (9.5 g,
13.9 mmol) was dissolved in DMF (100 ml) then dichloro-
methane (200 ml) was added. This organic solution was
washed with 1 M Na2CO3 (2 ꢂ 150 ml) and water (2 ꢂ 150 ml),
then dried (MgSO4), filtered and evaporated to yield the free
amine (5.7 g, 72% yield); mp 152–153 1C. ESMS (+ve) 569
1
(M+, 100%). IR(KBr, pellet, cmꢁ1) 1725 s, 1266 s. H NMR
(400 MHz, DMSO-d6) d 8.22 (m (AA0BB0), 12H, Ar–H), 4.52
(s, 6H, CH2), 2.34 (br. s, 2H, NH2). 13C NMR (100 MHz,
DMSO-d6) d 164.04 (CO2R), 150.22 (ArC–NO2), 134.74
(ArC–CO2R), 130.82 (ArC–H), 123.65 (ArC–H), 67.31
(CH2), 54.25 (Cq). Anal. calcd for C25H20N4O12: C, 52.82;
H, 3.55; N, 9.86. Found: C, 52.65; H, 3.49; N, 9.81%.
N-(tert-Butyloxycarbonyl)-1,1,1-tris(4-maleimidobenzoyloxy-
methyl)methylamine 6. 4-Maleimidobenzoic acid (12.0 g, 55.35
mmol) was gently refluxed in thionyl chloride (45 ml) with tert-
butyl catechol (0.01 g) and stirred for 2 hours under an
atmosphere of nitrogen. The solution was cooled to room
temperature, the excess thionyl chloride removed in vacuo and
the resulting solid dried under high vacuum. This solid was
gradually added, under an atmosphere of N2, to a solution of 2
(3.7 g, 16.8 mmol), tert-butyl catechol (0.01 g) and Et3N (20
ml, 144 mmol) in dichloromethane (200 ml). The reaction was
heated gently for 18 hours then cooled to room temperature
and filtered. The solution was washed with saturated aqueous
NaHCO3 (3 ꢂ 150 ml) and saturated aqueous NaCl (5 ꢂ 150
ml). The organic layer was dried (MgSO4), filtered and eva-
porated under reduced pressure. The crude product was
purified by column chromatography (10% ethyl acetate–
dichloromethane) and dried under high vacuum (6.9 g,
8.4 mmol, 50%); mp 113–116 1C. ESMS (+ve) 825 (MLi+,
100%), 841 (MNa+, 45%). IR(KBr, pellet, cmꢁ1) 3376 w,
1,1,1-Tris(4-methoxybenzoyloxymethyl)methylamine
tri-
fluoroacetic acid salt 9. This compound was prepared by a
procedure analogous to that used for the preparation of 7
using N-(tert-butyloxycarbonyl)-1,1,1-tris(4-methoxybenzoy-
loxymethyl)methylamine 4 (5.9 g, 9.5 mmol), dichloromethane
(20 ml) and trifluoroacetic acid (4 ml) (5.9 g, 98% yield); mp
150–151 1C. ESMS (ꢁve) 113 (CF3COOꢁ, 50%). ESMS (+ve)
524 (M+, 100%). IR(KBr, pellet, cmꢁ1) 1731 s, 1713 s, 1259 s.
1H NMR (400 MHz, DMSO-d6) d 9.06 (br. s, 3H, NH3+),
8.09 (m (AA0), 6H, Ar–H), 7.03 (m (XX0), 6H, Ar–H), 4.65
(s, 6H, CH2), 3.84 (s, 9H, O–CH3). 13C NMR (100 MHz, DMSO-
d6) d 164.88 (CO2R), 163.55 (ArC–OCH3), 131.96 (ArC–H),
120.92 (ArC–CO2R), 113.93 (ArC–H), 63.04 (CH2), 56.49 (Cq),
55.56 (O–CH3). Anal. calcd for C30H30F3NO11.2[H2O]: C, 53.49;
H, 5.09; N, 2.16. Found: C, 53.93; H, 4.50; N, 2.16%.
1,1,1-Tris(4-methoxybenzoyloxymethyl)methylamine
10.
This compound was prepared by a procedure analogous to
that used for the preparation of 8 using 9 (4.2 g, 6.7 mmol),
DMF (50 ml) and dichloromethane (250 ml) (2.8 g, 80%
yield); mp 93 1C. ESMS (+ve) 524 (M+, 90%). IR(KBr,
pellet, cmꢁ1) 3389 m, 2964 m, 1705 s, 1605 s, 1256 s. 1H NMR
(400 MHz, CDCl3) d 7.98 (m (AA0), 6H, Ar–H), 6.88 (m
(XX0), 6H, Ar–H), 4.48 (s, 6H, CH2), 3.83 (s, 9H, CH3), 1.79
(br. s, 2H, NH2). 13C NMR (100 MHz, CDCl3) d 165.94
(CO2R), 163.79 (ArC–OCH3), 131.91 (ArC–H), 121.99
(ArC–CO2R), 113.89 (ArC–H), 66.28 (CH2), 55.58 (CH3),
55.18 (Cq). Anal. calcd for C28H29NO9: C, 64.24; H, 5.58;
N, 2.68. Found: C, 64.12; H, 5.61; N, 2.65%.
1
3102 w, 2977 w, 1716 s, 1267 s. H NMR (400 MHz, DMSO-
d6) d 8.06 (m (AA0), 6H, Ar–H), 7.48 (m (XX0), 6H, Ar–H),
7.43 (br. s, 1H, NH), 7.22 (s, 6H, HCQCH), 4.76 (s, 6H, CH2),
1.36 (s, 9H, CH3). 13C NMR (100 MHz, DMSO-d6) d 169.43
(CQONCQO), 164.66 (CO2R), 154.71 (NH–CQO), 135.95
(ArC–NR), 134.86 (RHCQCHR), 129.90 (ArC–H), 128.02
(ArC–CO2R), 126.19 (ArC–H), 78.57 (Cq–CH3), 63.31 (CH2),
56.75 (Cq–CH2), 28.05 (C–CH3). Anal. calcd for
C42H34N4O14: C, 61.61; H, 4.19; N, 6.84. Found: C, 61.76;
H, 4.24; N, 6.87%.
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1,1,1-Tris(4-methylbenzoyloxymethyl)methylamine 11. N-(tert-
Butyloxycarbonyl)-1,1,1-tris(4-methylbenzoyloxymethyl)methyl-
amine 5 (5.4 g, 9.4 mmol) was dissolved in dichloromethane
(50 ml), trifluoroacetic acid (5 ml) was added and the solution
was refrigerated for 18 hours. The organic solution was washed
with 1 M Na2CO3 (2 ꢂ 150 ml) and water (2 ꢂ 150 ml), then
dried (MgSO4), filtered and evaporated to yield the free amine
(3.5 g, 77% yield); mp 119 1C. ESMS (+ve) 476 (M+, 100%),
483 (MLi+, 35%). IR(KBr, pellet, cmꢁ1) 3387 m, 2949 w, 1727 s,
1714 s, 1261 s. 1H NMR (400 MHz, DMSO-d6) d 7.86 (m (AA0),
6H, Ar–H), 7.26 (m (XX0), 6H, Ar–H), 4.39 (s, 6H, CH2), 2.36 (s,
9H, ArC–CH3), 2.14 (br. s, 2H, NH2). 13C NMR (100 MHz,
methyl)methylamine 4 (0.5 g, 0.7 mmol), dichloromethane
(10 ml), 4,40-methylenebis(phenyl isocyanate) 13 (0.09 g,
0.35 mmol) for 24 h. The product was isolated by filtration
as a white solid (0.33 g, 74%); mp 94.4–95 1C. ESMS (+ve)
1320 (MNa+, 50%), 1303 (MLi+, 45%). IR(KBr, pellet,
1
cmꢁ1) 3377 m, 3005 w, 2960 m, 2838 m, 1713 s, 1257 s. H
NMR(400 MHz, DMSO-d6) d 8.58 (br s, 2H NH), 7.90 (m
(AA0), 12H, Ar–H), 7.24 (m (AA0), 4H, core-Ar–H), 7.02 (m
(MM0), 4H, core-Ar–H), 6.97 (m (AA0), 12H, Ar–H), 6.67 (br.
s, 2H, NH), 4.74 (s,12H, CH2), 3.80 (s,18H, CH3), 3.75 (br. s,
2H, core-CH2) 13C NMR(100 MHz, DMSO-d6) d 164.95
(CO2R), 163.26 (ArC–OCH3), 154.68 (NHCQONH), 137.68
(core-ArC–NHR), 134.67 (ArC–CO2R), 131.39 (core-
ArC–H), 128.80 (core-ArC–CH2), 121.37 (p-CH3O–ArC–H),
118.02 (core-ArC–NHR), 113.95 (p-CH3O–ArC–H), 63.62
(CH2), 56.79 (Cq), 55.47 (CH3), 39.51 (core-CH2). Anal. calcd
for C71H68N4O20: C, 65.73; H, 5.28; N, 4.32. Found: C, 65.27;
H, 5.25; N, 4.03%.
DMSO-d6)
d 165.47 (CO2R), 143.67 (ArC–CH3), 129.33
(ArC–H), 129.18 (ArC–H), 126.66 (ArC–CO2R), 66.58 (CH2),
54.26 (Cq–CH2), 21.14 (ArC–CH3). Anal. calcd for C28H29NO6:
C, 70.72; H, 6.15; N, 2.95. Found: C, 70.76; H, 6.14; N, 2.98%.
1,1,1-Tris(4-maleimidobenzoyloxymethyl)methylamine
12.
This compound was prepared by a procedure analogous to
that used for the preparation of 11 using N-(tert-butyloxy-
carbonyl)-1,1,1-tris(4-maleimidobenzoyloxymethyl)methylamine
6 (1.1 g, 1.3 mmol), dichloromethane (20 ml) and trifluoroa-
cetic acid (1 ml) (0.84 g, 90% yield); mp 111 1C. ESMS (+ve)
(N0,N0 0 0 -Bis(1,1,1-tris(4-maleimidobenzoyloxymethyl)methyl))-
4,40-methylenebis(phenylurea) 16. This compound was pre-
pared by a procedure analogous to that used for the pre-
paration of 14 using 1,1,1-tris(4-maleimidobenzoyloxymethyl)
methylamine 6 (0.8 g, 1.1 mmol), dichloromethane (15 ml) and
added to a stirred solution of 4,40-methylenebis(phenyl iso-
cyanate) (0.14 g, 0.55 mmol) 13 for 48 hours. The solvents
were removed in vacuo to give the product as a bright yellow
solid (0.85 g, 92%); mp 153.5 1C. ESMS (+ve) 1710 (MNa+,
70%), 1694 (MLi+, 20%). IR(KBr, pellet, cmꢁ1) 3475 w, 3381
m, 3100 m, 2960 w, 1716 s, 1265 s. 1H NMR(400 MHz,
DMSO-d6) d 8.57 (br.s, 2H, NH), 8.05 (m (AA0), 12H,
Ar–H), 7.45 (m (XX0), 12H, Ar–H), 7.26 (m (AA0), 4H,
core-Ar–H), 7.20 (s, 12H, HCQCH), 6.69 (br. s, 2H, NH),
4.87 (s,12H, CH2), 3.75 (br. s, 2H, core-CH2). 13C NMR(100
Mhz, DMSO-d6) d 169.40 (OQCNCQO), 164.70 (CO2R),
154.72 (NHCQONH), 137.61 (core-ArC–H), 135.95
(ArC–NR2), 134.83 (RHCQCHR), 134.73 (ArC–CO2R),
129.91 (p-maleimide-ArC–H), 128.83 (core-ArC–CH2),
127.88 (core-ArC–H), 126.15 (p-maleimide-ArC–H), 118.19
(core-ArC–NHR), 64.16 (CH2), 56.76 (Cq), 39.51 coincident
with residual solvent (core-CH2). Anal. calcd for
C89H62N10O26: C, 63.35; H, 3.70; N, 8.30. Found: C, 62.46;
H, 3.72; N, 7.96%.
719 (M+, 100%), 725 (MLi+, 30%). IR(KBr, pellet, cmꢁ1
)
3475 w, 3102 w, 1716 s, 1265 s. 1H NMR (400 MHz, acetone-
d6) d 8.13 (m (AA0), 6H, Ar–H), 7.49 (m (XX0), 6H, Ar–H),
7.06 (s, 6H, HCQCH), 4.63 (s, 6H, CH2). 13C NMR (100
MHz, acetone-d6) d 170.19 (CQONCQO), 165.99 (CO2R),
137.30 (ArC–NR), 135.61 (RHCQCHR), 131.02 (ArC–H),
129.59 (ArC–CO2R), 126.80 (ArC–H), 68.10 (CH2), 55.65
(Cq–CH2). Anal. calcd for C37H26N4O12: C, 61.84; H, 3.65;
N, 7.80. Found: C, 61.62; H, 3.74; N, 7.59%.
(N0,N0 0 0 -Bis(1,1,1-tris(4-nitrobenzoyloxymethyl)methyl))-4,40-
methylenebis(phenylurea) 14. 1,1,1-Tris(4-nitrobenzoyloxy-
methyl)methylamine 8 (2.5 g, 4.4 mmol) was dissolved in dry
dichloromethane (35 ml) and added to a stirred solution of
4,40-methylenebis(phenyl isocyanate) 13 (0.6 g, 2.2 mmol) in
dichloromethane (20 ml). The reaction mixture was stirred
under an atmosphere of nitrogen at RT for 18 hours. The
product was isolated by filtration as an off-white solid (2.3 g,
75%); mp 149–151 1C. ESMS (+ve) 1409 (MNa+, 50%),
1393 (MLi+, 60%). IR(KBr, pellet, cmꢁ1) 3385 m, 3111 w,
1731 s, 1525 s, 1265 s. 1H NMR (400 MHz, DMSO-d6) d 8.48
(br s, 2H, NH), 8.20 (m (AA0), 12H, Ar–H), 8.16 (m (MM0),
12H, Ar–H), 7.19 (m (AA0), 4H, core-Ar–H), 6.97 (m (MM0),
4H, core-Ar–H), 6.74 (br s, 2H, NH), 4.86 (s, 12H, CH2), 3.69
(br s, 2H, core-CH2). 13C NMR(100 Mhz, DMSO-d6) d 163.88
(CO2R), 154.69 (NHCQONH), 150.28 (ArC–NO2), 137.55
(core-ArC–NHR), 134.82 (core-ArC–H),134.55 (ArC–CO2R),
130.77 (p-NO2-ArC–H), 128.8 (core-ArC–CH2), 123.73 (p-
NO2-ArC–H), 118.14 (core-ArC–H), 64.51(CH2), 56.65 (Cq),
39.51 coincident with residual solvent (core-CH2). Anal. calcd
for C65H50N10O26: C, 56.28; H, 3.63; N, 10.10. Found: C,
56.30; H, 3.65; N, 9.85%.
(N0,N0 0 0 -Bis(1,1,1-tris(4-aminobenzoyloxymethyl)methyl))-
4,40-methylenebis(phenylurea) 17. (N0,N0 0 0 -Bis(1,1,1-tris(4-ni-
trobenzoyloxymethyl)methyl)-4,40-methelenebis(phenylurea)
14 (1.8 g, 1.29 mmol) was dissolved in dry DMF (18 ml) and
0.18 g of 5% Pd/C was added. The reaction mixture was
pressurised with H2 gas (650 psi) and heated to 55 1C for
18 hours. The solution was filtered and evaporated under
reduced pressure to give a brown residue. The residue was
triturated with diethyl ether (3 ꢂ 20 ml) and dichloromethane
added to precipitate the product as a dark yellow solid. The
powder was collected by filtration and dried under high
vacuum to yield (0.97 g, 0.8 mmol, 62%); mp 164–165.6 1C.
ESMS (+ve) 1229 (MNa+, 100%), 1213 (MLi+, 100%).
(HRMS) Found 1207.4490. C64H63N10O14(+) requires
1207.4519. IR(KBr, pellet, cmꢁ1) 3365 m, 3955 w, 2358 w,
(N0,N0 0 0 -Bis(1,1,1-tris(4-methoxybenzoyloxymethyl)methyl))-
4,40-methylenebis(phenylurea) 15. This compound was
prepared by a procedure analogous to that used for the
preparation of 14 using 1,1,1-tris(4-methoxybenzoyloxy-
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1
1698 s, 1601 s. H NMR(400 MHz, DMSO-d6) d 8.55 (br. s,
and dry toluene (5 ml), 1,1,1-tris(4-methylbenzoyloxymethyl)-
methylamine 11 (0.43 g, 0.9 mmol) and dichloromethane (10
ml) (0.47 g, 0.29 mmol, 97%); mp 111–112 1C. (ESMS+) 1634
(MLi+, 100%), 1650 (MNa+, 100%). Anal. calcd for
C93H90N6O21: C, 68.62; H, 5.57; N, 5.16. Found: C, 68.63;
H, 5.78; N, 5.02%. IR(KBr, pellet, cmꢁ1) 3392 m, 1718 s,
2H, NH), 7.65 (m (AA0), 12H, Ar–H), 7.23 (m (AA0), 4H,
core-Ar–H), 7.02 (m (XX0), 4H, core-Ar–H), 6.53 (m (XX0),
12H, Ar–H), 6.50 (br. s, 2H, NH), 5.99 (br. s, 12H, Ar–NH2),
4.60 (s, 12H, CH2), 3.75 (br. s, 2H, core-CH2). 13C NMR(100
MHz, DMSO-d6) d 165.45 (CO2R), 154.67 (NHCQONH),
153.71 (ArC–NH2), 137.74 (core-ArC–H), 134.54 (ArC–CO2),
131.28 (core-ArC–H), 128.83 (core-ArC–CH2), 117.96
(core-ArC–NHR), 115.21 (p-NH2–ArC–H), 112.59 (p-NH2–
ArC–H), 62.88 (CH2), 56.94 (Cq), 39.51 coincident with
residual solvent (core-CH2).
1
1268 s. H NMR (400 MHz, DMSO-d6) d 8.14 (s, 3H, NH),
7.91 (m (AA0), 18H, p-CH3–Ar–H), 7.28 (s, 3H, core-Ar–H),
7.25 (m (XX0), 18H, p-CH3–Ar–H), 6.30 (s, 3H, NH), 4.93 (s,
18H, CH2), 2.37 (s, 27H, CH3). 13C NMR (100 MHz, DMSO-
d6)
d
166.49 (CO2R), 155.58 (NHCQONH), 144.90
(ArC–CH3), 141.64 (ArC–NHR), 130.52 (p-CH3–ArC–H),
130.10 (p-CH3-ArC–H), 128.08 (ArC–CO2R), 102.57 (core-
ArC–H), 64.94 (CH2), 58.53 (Cq), 21.66 (CH3).
1,3,5-Tris((1,1,1-tris(4-nitrobenzoyloxymethyl)methylamino)
carbonylamino)benzene 21. 1,3,5-Benzenetricarbonyl triazide
19 (0.09 g, 0.3 mmol) was dissolved in dry toluene (5 ml)
and refluxed for one hour under an atmosphere of nitrogen.
The reaction was allowed to cool, the toluene was removed on
a rotary evaporator and 1,1,1-tris(4-nitrobenzoyloxymethyl)-
methylamine 8 (0.52 g, 0.9 mmol) dissolved in CH2Cl2 (10 ml)
was added under an atmosphere of nitrogen. The reaction
mixture was gently refluxed for 16 hours and cooled to room
temperature. The resulting precipitate was collected by filtra-
tion affording a yellow powder (0.53 g, 92% yield); mp
143–1451 C. (ESMS+) 1929 (MNa+, %). Anal. calcd for
C84H63N15O39: C, 52.92; H, 3.33; N, 11.02. Found: C, 52.79;
H, 3.41; N, 10.84%. IR(KBr, pellet, cmꢁ1) 3397 m, 1733 s. 1H
NMR (400 MHz, acetone-d6) 8.23 (m (AA0BB0), 36H, p-NO2-
Ar–H), 8.08 (br. s, 3H, NH), 7.22 (s, 3H, core-Ar–H), 6.43 (br.
s, 3H, NH), 5.07 (s, 18H, CH2). 13C NMR (100 MHz, acetone-
1,3,5-Tris((1,1,1-tris(4-maleimidobenzoyloxymethyl)methyl-
amino)carbonylamino)benzene 24. This compound was pre-
pared by a procedure analogous to that used for the prepara-
tion of 22 using 1,3,5-benzenetricarbonyl triazide 19 (0.04 g,
0.15 mmol) and dry toluene (3 ml), 1,1,1-tris(4-maleimidoben-
zoyloxymethyl)methylamine 12 (0.32 g, 0.45 mmol) and di-
chloromethane (10 ml) to yield a yellow solid (0.35 g, 0.15
mmol, 99%); mp 200 1C. IR(KBr, pellet, cmꢁ1). 1H NMR (400
MHz, DMSO-d6) d 8.80 (br. s, 3H, NH), 8.04 (m (AA0), 18H,
Ar–H), 7.44 (m (XX0), 18H, Ar–H), 7.22 (s, 3H, core-Ar–H),
7.19 (s, 18H, HCQCH), 6.53 (br. s, 3H, NH), 4.87 (s, 18H,
CH2). 3C NMR (100 MHz, DMSO-d6)
d
169.4
(CQONCQO), 164.69 (CO2R), 154.55 (NHCQONH),
140.43 (core-ArC–NHR), 135.96 (ArC–NR2), 134.83
d6)
d
165.03 (CO2R), 155.67 (NHCQONH), 151.70
(RHCQCHR),
129.93
(p-maleimide-ArC–H),
127.85
(ArC–NO2), 141.47 (ArC–NHR), 135.96 (ArC–CO2R),
131.83 (p-NO2–ArC–H), 124.51 (p-NO2–ArC–H), 103.43
(core-ArC–H), 65.73 (CH2), 58.50 (Cq).
(ArC–CO2R), 126.15 (p-maleimide-ArC–H), 100.57 (core-
ArC–H), 64.20 (CH2), 56.70 (Cq). Anal. calcd for
C120H81N15O39.H2O: C, 60.69; H, 3.52; N, 8.85. Found: C,
60.43; H, 3.71; N, 8.71%.
1,3,5-Tris((1,1,1-tris(4-methoxybenzoyloxymethyl)methylamino)
carbonylamino)benzene 22. This compound was prepared by a
procedure analogous to that used for the preparation of 21
using 1,3,5-benzenetricarbonyl triazide 19 (0.15 g, 0.52 mmol)
and dry toluene (7 ml), 1,1,1-tris(4-methoxybenzoyloxy-
methyl)methylamine 10 (0.82 g, 1.56 mmol) and dichloro-
methane (15 ml). The reaction mixture was gently refluxed
for 16 hours and cooled to room temperature. The solvent was
removed by rotary evaporation to yield a white solid (0.89 g,
0.50 mmol, 96%); mp 114–115 1C. (ESMS+) 1778 (MLi+,
100%), 1794 (MNa+, 100%). Anal. calcd for C93H90N6O30:
C, 63.05; H, 5.12; N, 4.74. Found: C, 63.09; H, 5.29; N, 4.74%.
IR(KBr, pellet, cmꢁ1) 3384 m, 2962 w, 1717 s, 1258 s.
1H NMR (400 MHz, acetone-d6) d 8.15 (s, 3H, NH), 7.97
(m (AA0), 18H, p-CH3O–Ar–H), 7.30 (s, 3H, core-Ar–H), 6.96
(m (XX0), 18H, p-CH3O–Ar–H), 6.28 (s, 3H, NH), 4.90 (s,
18H, CH2), 3.86 (s, 27H, CH3). 13C NMR (100 MHz, acetone-
1,3,5-Tris((1,1,1-tris(4-aminobenzoyloxymethyl)-methylamino)
-carbonylamino)benzene 25. 1,3,5-Tris((1,1,1-tris(4-nitroben-
zoyloxymethyl)methylamino) carbonyl-amino)benzene 21
(400 mg, 0.2 mmol) was dissolved in dry DMF (5 ml) and
0.04 g of 5% Pd/C was added. The reaction mixture was
pressurised with H2 gas (650 psi) and heated to 55 1C for
15 hours. The solution was filtered and evaporated under re-
duced pressure to give a brown oil that was solidified by the
addition of dichloromethane, collected by filtration and dried
under high vacuum to yield a yellow solid (0.21 g, 0.13 mmol,
65%); mp 258–260 1C. (HRMS) Found 1636.5692. C84H82
N15O21(+) requires 1636.5804. IR(KBr, pellet, cmꢁ1) 3368 m,
1700 s, 1602 s, 1268 s. 1H NMR (400 MHz, DMSO-d6) d 8.72
(br, s, 3H, NH), 7.65 (m (AA0), 18H, Ar–H), 7.15 (s, 3H, core-
Ar–H), 6.53 (m (XX0), 18H, Ar–H), 6.37 (br, s, 3H, NH), 5.98 (s,
18H, NH2), 4.60 (s, 18H, CH2). 13C NMR (100 MHz) d 165.44
(CO2R), 154.48 (NHCQONH), 153.70 (ArC–NH2), 140.51
(core-ArC–NHR), 131.29 (pNH2–ArC–H), 115.18 (pNH2–
ArC–H), 112.62 (core-ArC–H), 62.89 (CH2), 56.87 (Cq).
d6)
d
166.17 (CO2R), 164.73 (ArC–OCH3), 155.61
(NHCQONH), 141.70 (ArC–NHR), 132.55 (p-CH3O–ArC–H),
123.02 (ArC–CO2R), 114.73 (p-CH3O–ArC–H), 102.56 (core-
ArC–H), 64.87 (CH2), 58.57 (Cq), 56.01 (CH3).
1,3,5-Tris((1,1,1-tris(4-hydroxybenzoyloxymethyl)methylamino)
carbonylamino)benzene 26. A solution of aluminium bromide
(1.01 g, 3.8 mmol) and dodecanethiol (2 ml) in dry DCM
(7 ml) was cooled in an ice bath under an atmosphere of N2.
1,3,5-Tris((1,1,1-tris(4-
1,3,5-Tris((1,1,1-tris(4-methylbenzoyloxymethyl)methylamino)
carbonylamino)benzene 23. This compound was prepared by a
procedure analogous to that used for the preparation of 22
using 1,3,5-benzenetricarbonyl triazide 19 (0.09 g, 0.3 mmol)
ꢀc
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methoxybenzoyloxymethyl)methylamino)carbonylamino)ben-
zene 22 (0.25 g, 0.14 mmol) was added as a solid and the
reaction warmed to room temperature and stirred for 16
hours. The reaction mixture was poured into water (250 ml)
and acidified with 1 M HCl. The aqueous solution was
extracted with DCM (200 ml) that was set aside then the
aqueous layer was filtered to collect the precipitated white
solid (0.20 g, 0.12 mmol, 87%); mp 168–169 1C. (HRMS [M-
2H]2ꢁ) Found 821.2094. C84H70N6O30(ꢁ2) requires 821.2073
IR(KBr, pellet, cmꢁ1) 3383 br, 1698 s, 1608 s, 1270 s. 1H NMR
(400 MHz, DMSO-d6) d 10.35 (s, 9H, OH), 8.74 (s, 3H, NH),
7.82 (m (AA0), 18H, p-OH–Ar–H), 7.17 (s, 3H, core-Ar–H),
6.80 (m (XX0), 18H, p-OH–Ar–H), 6.46 (s, 3H, NH), 4.70 (s,
18H, CH2). 13C NMR (100 MHz, DMSO-d6) d 165.15
(CO2R), 162.20 (ArC–OH), 154.51 (NHCQONH), 140.50
(core-ArC–NHR), 131.66 (p-OH-ArC–H), 119.80 (ArC
–CO2R), 115.35 (pOH–ArC–H), 100.15 (core-ArC–H), 63.51
(CH2), 56.76 (Cq).
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162 | New J. Chem., 2007, 31, 155–162