Dendrimers based on melamine. Divergent and orthogonal, convergent syntheses of a G3 dendrimer

Article abstract of DOI:10.1021/ol005585g

(figure preaented) Both convergent and divergent strategies are used to synthesize 1, a dendrimer comprising triazines linked by diamines. The convergent approach is orthogonal; neither protecting groups nor functional group manipulations are required using the building blocks selected.

Full text of DOI:10.1021/ol005585g

ORGANIC
LETTERS
2000
Vol. 2, No. 6
843-845
Dendrimers Based on Melamine.
Divergent and Orthogonal, Convergent
Syntheses of a G3 Dendrimer
Wen Zhang and Eric E. Simanek*
Department of Chemistry, Texas A&M UniVersity, College Station, Texas 77845
simanek@mail.chem.tamu.edu
Received January 26, 2000
ABSTRACT
Both convergent and divergent strategies are used to synthesize 1, a dendrimer comprising triazines linked by diamines. The convergent
approach is orthogonal; neither protecting groups nor functional group manipulations are required using the building blocks selected.
We report the convergent and divergent syntheses of 1, a
third generation (G3) dendrimer (MW > 5000) comprising
melamine, which presents 16 carbamate groups on the
periphery. Incorporating melamine groups into dendrimers1
offers opportunities (i) to exploit the differential reactivity
of triazines, (ii) to prepare dendrimers of significant structural
diversity (based both on the number of diamines available
and the ability to manipulate their placement within the
structure), and (iii) to introduce domains for molecular
recognition.2,3 Molecule 1 was selected as a target because
it is small enough to be prepared by both convergent4 and
divergent5,6 methods. We find that 1 can be obtained in high
yields and purity using the convergent method. The divergent
method provides 1, but upon separation from side products,
less than 1% overall yield is realized.
The divergent synthesis of 1 (Scheme 1) relies on
sequential additions of intermediate 2 to core structures
(ethylenediamine, then 4, then 6). Only two reactions,
Scheme 1. Divergent Synthesis of 1a
(1) For recent reviews of dendrimer chemistry, see: (a) Newkome, G.
R.; Moorefield, C. N.; Vogtle, F. Dendritic Macromolecules; VCH: New
York, 1996. (b) Newkome, G. R.; He, E.; Moorefield, C. N. Chem. ReV.
1999, 99, 1689. (c) Frechet, J. M. J. Science 1994, 263, 1710. (d) Fisher,
M.; Vogtle, F. Angew. Chem., Int. Ed. Engl. 1999, 38, 4000. (e) Bosman,
A. W.; Janssen, H. M.; Meijer, E. J. Chem. ReV. 1999, 99, 1665.
(2) For a review of molecular recognition using melamine, see: White-
sides, G. M.; Simanek, E. E.; Mathias, J. P.; Seto, C. T.; Chin, D. N.;
Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995, 28, 37 and references
therein.
(3) Newkome and co-workers have incorporated 1,5-diaminopyridine
units into dendrimers and examined the ability of these molecules to
recognize barbituric acid derivatives: Newkome, G. R.; Woolsey, B. D.;
He, E.; Moorefield, C. N.; Guther, R.; Baker, G. R.; Escamilla, G. H.; Merill,
J.; Luftmann, H. Chem. Commun. 1996, 2737.
a Reagents and conditions: (a) Hunig’s base; p-Boc-amino-
methyl-aniline; 0-25 °C. (b) Hunig’s base; ethylenediamine; 100
°C. (c) TFA. (d) Hunig’s base; 2; 80 °C.
(4) Hawker, C. J.; Frechet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
10.1021/ol005585g CCC: $19.00 © 2000 American Chemical Society
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deprotection and coupling, are required for each new
generation of dendrimers (G1 ) 3; G2 ) 5; G3 ) 1).
However, as the generation number increases, our ability to
(i) identify defects, (ii) separate the desired product from
side products resulting from incomplete reactions, and (iii)
obtain product in reasonable yields all become increasingly
difficult.
Scheme 3. Regioselective Reaction of p-Aminobenzylamine
The reactivities of these dendrimers differ with their size.
Most noteworthy are the differences in the rates of depro-
tection of the BOC group as monitored by the disappearance
1
of the t-Bu line in the H NMR. Whereas the deprotection
Dendrons 2 and 7-11 are soluble in a range of common
organic solvents, thus allowing purification by silica gel
chromatography. Compared with the divergent approach, this
route provides large amounts of pure material and has
become our method of choice for preparing dendrimers.
Molecule 1 can be obtained from 10 directly, or indirectly
through 11. Intermediate 11 can be isolated and characterized
by NMR and size exclusion chromatography. Both routes
proceed in very similar yields, and accordingly, we prefer
the one-pot method.
of 3 requires 2 h, deprotection of 5 requires 24 h under
identical conditions (1:1 TFA/CH2Cl2). Complete deprotec-
tion of 1 requires 5 days. Molecules 1, 3, and 5 show excel-
lent solubility in DMSO and mixtures of CH3OH/CH2Cl2.
Although the presence of 1 can be confirmed by NMR,
mass spectrometry, and size exclusion chromatography, we
have been unsuccessful in developing strategies for its
preparation on large scales because of low yields in the final
steps of the synthesis.
1
The convergent route to 1 relies on adding p-amino-
benzylamine and cyanuric chloride to the dendron in an
iterative fashion (Scheme 2). The use of p-aminobenzylamine
Consistent with our previous experience, the H NMR
spectra of polymelamines in CDCl3 provides little useful
information because of the existence of rotational isomers.2
In DMSO-d6, however, lines, especially the benzylic lines,
can be used to watch the iterative process. Three different
types of benzylic groups are seen (peripheral, close to BOC;
internal with a monochlorotriazine; internal with a free
aniline).
Scheme 2. Convergent Synthesis of 1a
The 13C NMR is more useful. The shifts of the aromatic
carbons of both the p-aminobenzylamine and the triazine
groups are dependent on the substitution pattern of the
triazine.9 Thus, the monochlorotriazines 2, 8,10 and 1010 show
spectra different than those of amines 7, 9, and 11 (Figure
1).
Most useful to us are the carbons “f” and “c” of the p-
aminobenzylamine group. When attached to a monochloro-
triazine (i.e., 2), these lines appear close together (136 and
137 ppm). When attached to a trisubstituted triazine (i.e.,
7), these lines separate to 134 and 138 ppm). Thus,
intermediate 8, which has one monochlorotriazine and two
trisubsituted triazines, shows both features in approximately
a 2:1 ratio. The inner pair of lines disappears in 9, as the
chlorine atom is replaced with p-aminobenzylamine. These
lines reappear in 10, but in a 6:1 ratio reflecting the ratio of
trisubstituted triazines to monochlorotriazine groups.
a Reagents and conditions: (a) Hunig’s base; p-aminobenzyl-
amine; 70 °C. (b) Hunig’s base; C3N3Cl3; 0-25 °C. (c) Ethylene-
diamine; Hunig’s base; 100 °C. (d) Excess ethylenediamine;
Hunig’s base; 100 °C. (e) 10; Hunig’s base; 100 °C.
to connect triazine groups is noteworthy; differences in
nucleophilicity of the two amino groups allow us to exploit
reactivity to achieve an orthogonal, convergent synthesis of
1 instead of relying on functional group interconversions or
protecting group manipulations. Only a limited number of
orthogonal routes to dendrimers have been reported. In
contrast to our strategy, these routes rely on orthogonal
synthetic tranformations.7,8
Reaction of the benzylic amine (over the aniline NH2) is
further enhanced by performing these substitutions on the
deactivated, disubstituted monochlorotriazine (Scheme 3).
Only one product, 7, is observed by 1H NMR when
p-aminobenzylamine is reacted with 2 at 70° C in THF.
Performing this reaction at 100° C in dioxane leads to a 4:1
mixture of 7 and 12.
(5) Tomalia, D. A.; Durst, H. D. Top. Curr. Chem. 1993, 165, 193.
(6) Moorefield, C. N.; Newkome, G. R.; Baker, G. R. Aldrichimica Acta
1992, 25, 31.
(7) Zimmerman employs alternating Mitsunobu esterifications and
Sonogashira couplings (of terminal acetylenes with aryl iodides) to build
G4 and G6 dendrimers; see: Zeng, F.; Zimmerman, S. C. J. Am. Chem.
Soc. 1996, 118, 5326.
(8) Frechet’s strategy relies on alternating carboxylate alkylations and
DCC-mediated esterifications to build G4 dendrimers; see: (a) Spindler,
R.; Frechet, J. M. J. J. Chem. Soc., Perkins Trans. 1 1993, 913. (b) Freeman,
A. W.; Frechet, J. M. J. Org. Lett. 1999, 1, 685.
(9) Spectra were obtained on a 400 MHz Varian instrument using typical
13C parameters. DMSO-d6 is the solvent for all molecules except 9. The
spectrum of 9 in CDCl3 is shown to illustrate the generality of the pattern
of lines; slight deviations in chemical shift can be seen.
(10) Lines corresponding to “a” for both 8 and 10 are not discernible in
Figure 1. These peaks both appear at 169 ppm.
844
Org. Lett., Vol. 2, No. 6, 2000

Figure 2. Traces were obtained on an HPLC apparatus equipped
with a Jordi gel column (divinylbenzene, 500 Å pore size) using
THF as a solvent (1.5 mL/min.) The retention times are 11.1 min
(1), 13.9 min (5), 15.2 min (3).
measurements are consistent with these observations and are
1.08, 1.16, and 1.80 for 3, 5, and 1, respectively. Beyond
the tailing of 1 by SEC, we have no evidence for the
existence of impurities in samples derived using the con-
vergent strategy. The potential impurities of 1, molecules
10 and/or 11, give different retention times by SEC. They
appear between 5 and 1, so their presence cannot be
discounted solely using this technique. Both 13C NMR and
mass spectrometry suggest that 1 is pure within the detection
limits of these techniques. Also noteworthy is that 10, 11,
and 1 are separable by silica gel chromatography.
We are left with three explanations for the observed tailing
in the size exclusion traces: trace impurities not identified
with the available techniques; aggregation events on the
column; absorption events on the column. We are examining
the behavior of these molecules as a function of concentration
and solvent and cannot yet eliminate these possibilities.
All molecules gave satisfactory mass spectra. With the
exception of 1, little fragmentation of the molecular ion was
observed. The fragmentation pattern produced by 1, which
appears to be loss of BOC followed by reaction of the
resulting amine, is under investigation.
Figure 1. The 13C NMR of 1 and intermediates.
Acknowledgment. This work was supported by Texas
A&M University and the Welch Foundation (A-1430). The
mass spectrometry facility at Texas A&M University is
supported by the NSF (CHE 8709657). We thank Dr. David
Bergbreiter and Mr. Brain Walchuk for use of their apparatus
for size exclusion chromatography and assistance with its
operation.
Figure 2 shows the traces of the three generations of
dendrimers. The width of each peak increases with increasing
size of the molecule. Impurities can be identified in the trace
produced by size exclusion chromatography at the G2 (5)
stage (indicated with an arrow in Figure 2). These impurities
can be removed with chromatography to provide material
that shows a single ion by mass spectrometry and appears
pure by 13C NMR.
If impurities are present in the trace of 1 (obtained through
the convergent method, not from 5), they cannot be identi-
fied. However, the tailing of the trace toward longer retention
times is highly suggestive of their presence. Polydispersity
Supporting Information Available: Detailed experi-
mental procedures. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL005585G
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