Dendrimers terminated with dichlorotriazine groups provide a route to compositional diversity

Article abstract of DOI:10.1021/ol400811h

Triazine dendrimers terminated with either four or eight dichlorotriazines can be prepared in high yields by reacting an amine-terminated dendrimer with cyanuric chloride. These materials exist as white powders and are stable to storage at room temperature. Sequential nucleophilic aromatic substitution with two different amine nucleophiles yields compounds that display the desired compositional diversity. Reaction conditions for the substitution were developed using a model dichlorotriazine with amine nucleophiles at -20, 0, and 25 C. Selective substitution is favored at lower temperatures and with more nucleophilic amine groups.

Full text of DOI:10.1021/ol400811h

ORGANIC
LETTERS
2013
Vol. 15, No. 15
3808–3811
Dendrimers Terminated with
Dichlorotriazine Groups Provide
a Route to Compositional Diversity
Subrata Patra,† Brittany Kozura,† Adela Y.-T. Huang,‡ Alan E. Enciso,† Xiankai Sun,§
Jer-Tsong Hsieh, Chai-Lin Kao,‡ Hui-Ting Chen,^ and Eric E. Simanek*,†
Department of Chemistry, Texas Christian University, Fort Worth, Texas 76129,
United States, Department of Medicinal and Applied Chemistry, Kaohsiung Medical
University, Kaohsiung, Taiwan, Department of Radiology, University of Texas
Southwestern Medical Center, Dallas, Texas 75390, United States, Department of
Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390,
United States, and Department of Fragrance and Cosmetic Science, Kaohsiung Medical
University, Kaohsiung, Taiwan
e.simanek@tcu.edu
Received March 25, 2013
ABSTRACT
Triazine dendrimers terminated with either four or eight dichlorotriazines can be prepared in high yields by reacting an amine-terminated
dendrimer with cyanuric chloride. These materials exist as white powders and are stable to storage at room temperature. Sequential nucleophilic
aromatic substitution with two different amine nucleophiles yields compounds that display the desired compositional diversity. Reaction
conditions for the substitution were developed using a model dichlorotriazine with amine nucleophiles at À20, 0, and 25 ꢀC. Selective substitution
is favored at lower temperatures and with more nucleophilic amine groups.
The generation of compositional diversity on the per-
iphery of dendrimers is a long-standing goal of the
community.1 The easiest route to this end is to apply
substoichiometric derivatization of dendrimers bearing a
common reactive surface group such as an amine.2 While
this strategy benefits from a low synthetic burden, the
result is a diversity of products that can present challenges
to the characterization. Methods for characterizing such
mixtures, however, are becoming increasingly refined.3
Using convergent synthetic approaches,4 dendrimers with
† Department of Chemistry, Texas Christian University.
‡ Department of Medicinal and Applied Chemistry, Kaohsiung Medical
University.
§ Department of Radiology, University of Texas Southwestern Medical Center.
Department of Urology, University of Texas Southwestern Medical Center.
^ Department of Fragrance and Cosmetic Science, Kaohsiung Medical
University.
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1135–1145.
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r
10.1021/ol400811h
Published on Web 07/19/2013
2013 American Chemical Society

specific compositional diversity can be obtained across a
variety of platforms including aryl5 and aliphatic6 ethers,
PAMAM,7 and triazines8 by carrying the diversity-
generating groups through the entire synthesis. Here, the
synthetic burden is substantially increased and the versa-
tility can be limited by the initial choice of the diversity
elements. Oftentimes, these products are derived from
the dimerization of dendrons displaying two different sur-
face chemistries6a including those relying on selective click
chemistry.7 Recently, Rudick reported that a three-com-
ponent Passerini coupling reaction has been efficiently
utilized to generate triblock dendrimers of low generations
from dendrons functionalized at the focus.9 Still, the
diversity elements are carried through the convergent
synthesis. Divergent strategies to dendrimers offer compel-
ling advantages over convergent routes. Divergent routes
provide access to larger dendrimers and benefit from mole
conservation. That is, multimerizations do not reduce the
number of moles of product theoretically available, and
instead, mass is added throughout the synthesis. Generat-
ing diversity using this strategy is challenging and can
introduce additional synthetic burden (vide infra). Mixed
approaches, as representative of recent work of Weck,
have yielded structurally diverse platforms.10
targets.11 Early efforts to generate compositional diversity
to make a dendrimer with a unique site on the periphery8a
or to install different orthogonal protecting groups both
relied on a convergent synthetic strategy.8b Thayumanavan
has generated similarly diverse targets using arylethers.5cÀe
We have achieved diversity by reacting poly(amine)
dendrimers with functionalized mono-14 or dichloro-
triazine groups.15 Although these methods have been
applied during divergent syntheses of low generation
dendrimers, these still require the separate synthesis of
the diversity-generating mono- or dichlorotriazine. Ac-
cordingly, we have historically avoided the synthesis of
large libraries of compounds. Our explorations of small
libraries have focused on either stoichiometric functiona-
lization of peripheral amines16 or the laborious substitu-
tion of internal linking amine groups17 in order to execute
the desired structureÀproperty relationship studies.
Triazines have been used for small molecule libraries.18
Extrapolating to dendrimers, however, requires two chal-
lenges to be overcome. First, a reactive dendrimer in the
form of a poly(dichlorotriazine) must be prepared and
established as a stable and viable intermediate. Second,
conditions for the selective, stepwise functionlization of
these molecules must be developed. Here, we report that
both challenges have been met.
We describe a strategy wherein amine-terminated den-
drimers are reacted with cyanuric chloride to yield poly
(dichlorotriazine) targets. These intermediates are sub-
jected to stepwise substitution of the triazine rings with two
different nucleophiles to yield targets that display these nu-
cleophiles in a 1:1 ratio. Accordingly, this chemistry represents
the first step necessary to efficiently prepare libraries from
the wealth of commercially available amine nucleophiles.
We find that the desired poly(dichlorotriazine) targets
are readily accessible. Dendrimers 1 and 2 display either 4
or 8 dichlorotriazines on the surface, respectively (Figure 1).
Both compounds are white powders that can be stored for
months at rt.
Our interest in triazine dendrimers is fueled, in part, by
the ease at which stepwise substitution of trichlorotriazine
occurs with amine nucleophiles.11 By controlling the reac-
tion temperature, trisubstituted triazines can be readily
accessed in good yields, purity, and at large scale.12 We
have invested significant energies in understanding the
relative reactivity of amine nucleophiles for triazines13
and used these methods to generate a range of dendrimer
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M. A.; Librizzi, D.; Samsonova, O.; Dicke, T.; Sproat, B.; Garn, H.;
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983. (c) Mintzer, M. A.; Merkel, O. M.; Kissel, T.; Simanek, E. E. New J.
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Figure 1. Targets.
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Org. Lett., Vol. 15, No. 15, 2013
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The synthesis starts with the preparation of monomer 3
which presents two BOC-protected piperazine groups and
a trismethylene dipiperidine amine (Scheme 1).19 Cyclic
secondary amines were chosen for both their high reactiv-
ity during nucleophilicaromaticsubstitution of thetriazine
ring and the perceived solubility advantages deriving from
a lack of H-bond donating groups. The reaction of 3 with a
dichlorotriazine displaying an alkyne group (reagent 4,
Scheme 1) yields 5. Upon deprotection with 2:1 methanol:
conc. HCl, the penultimate intermediate 6 is obtained.
Dendrimer 1 is realized by reacting 6 with 12 equiv of
cyanuric chloride;a 3-fold excess;in tetrahydrofuran at
À20 ꢀC for 4 h. Evidence for the formation of crosslinked
sideproducts is not observed by mass spectrometry or
NMR spectroscopy. Intramolecular cross-links to yield a
monochlorotriazine should present a mass defect equiva-
lent to C3N3Cl3. Intermolecular cross-links will yield spe-
cies with higher molecular weights.
Similarly, the synthesis of dendrimer 2 commences with
the reaction of 3 with 0.5 equiv of cyanuric chloride to yield
7. In a subsequent reaction, the linking diamine was added
to provide 8. The reaction of 8 with reagent 4 yields 9.
Deprotection of 9 provides 10, which is reacted with
cyanuric chloride under similar conditions to provide 2.
Dendrimers 1 and 2 and most intermediates are isolated
by conventional silica gel chromatography and character-
ized by NMR spectroscopy and mass spectrometry. All of
these intermediates are stable at room temperature.
To evaluate conditions for achieving selective substitu-
tion of these dendrimers, 4 was used as a model.20 Using 1
equiv of an amine nucleophile, the ratio of desired single
substitution A and undesired double substitution B could
be assessed as a function of temperature upon isolating the
product of the reaction (Scheme 2). The reactions were
executed for 4 h at the prescribed temperatures using 1
equiv of diisopropylethylamine at 0.03 M 4 in a 2:1
tetrahydrofuran/dichloromethane mixture. The solvent
mixture was required due to solubility challenges encoun-
tered with the methyl ester of proline (entry 8 in Table 1).
Table 1 summarizes the results of these experiments. The
amines in this table are organized from least reactive to
most reactive as would be predicted from our earlier
studies.11 This reactivity prediction excludes steric effects
deriving from substituents on the carbon adjacent to the
nucleophilic nitrogen (entries 6À8). These encumbered
amines clearly react more sluggishly than their unsubsti-
tuted analogues. The impact that steric encumberance has
on five-membered rings over six-membered rings is pro-
nounced as the former do not react completely in the time
provided.
Scheme 2. Reaction of Alkyne Dichlorotriazine with
Nucleophile
Scheme 1. Synthesis of Poly(dichlorotriazine) Dendrimers 1and 2a
Many lessons emerge from these studies. First, as the
observed nucleophilicity of the amine increases, selectivity
also increases. Second, the ratio of A:B is maximized at low
temperature. Third, steric congestion near the nucleophilic
nitrogen has pronounced effects on the rate and selectivity of
the reaction. Methanol is unreactive under these conditions.
Table 1. Product Distribution Reported As the Ratio of
Monosubstituted/Disubstituted at Three Temperatures after
4 h of Reaction
a TMD is trismethylene dipiperidine.
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2002, 35, 9015–9021.
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E. M.; Khersonsky, S. M.; Luzung, M. R.; Walsh, D. P.; Xiong, W.;
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a Remainder isolated as unreacted 4.
With these results in hand, we pursued selective
substitution of dendrimers 1 and 2. The HEEP
(20) Banerjee, R.; Pace, N. J.; Brown, D. R.; Weerapana, E. J. Am.
Chem. Soc. 2013, 135, 2497–2500.
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Org. Lett., Vol. 15, No. 15, 2013

species than the hydrophobic alternatives. Using identical
reaction conditions to the model studies, compounds 11
and 12 were obtained. These intermediates could be iso-
lated by silica gel chromatography in 85% and 79% yields,
respectively. These yields exceed what would be expected
based on the model studies (0.944 = 78%; 0.948 = 61%)
reflecting higher selectivity under the conditions employed, or
an inability to detect side reactions including oversubstitution.
Figure 2 shows the derivatives of 11 and 12 (identified
aÀc) that were prepared using aminoethoxyethanol,
4-aminomethylpiperidine and proline methylester as nu-
cleophiles. The reaction progress can be monitored by
mass spectrometry, and the major species that were identi-
fied corresponds to the desired target. These traces appear
in Figure 2. Data derived from mass spectrometry are
compiled and include the calculated (calcd) and observed
(found) ions.
Not surprisingly, evidence for the incomplete reaction of
11 and 12 with the proline methyl ester to yield 11c and 12c
is seen in the mass spectrum in the crude samples.
In summary, the poly(dichlorotriazine) dendrimers are
viable synthetic targets that exist as stable, white powders.
These molecules react with commercially available amine
nucleophiles to yield diversity in well-defined ratios. While
demonstrated on triazine dendrimer platforms, this strat-
egy should be applicable to most amine terminated den-
drimers. These results open the possibility for the
preparation of larger libraries of dendrimers for more
detailed structureÀactivity relationship studies.
Acknowledgment. This work was supported by NIH
1R01CA 159144-01 and the Welch Foundation (A-0008).
Figure 2. ESI mass spectrograms of dendrimer derivatives.
(1-[2-[2-hydroxyethoxy)ethyl]-piperazine) group was installed
as a common surface group, as the amine conveys solubility
and the PEG-like tail is hypothesized to reduce the cyto-
toxicity of the cation should these molecules ever be
assessed in cell culture. These benefits outweighed factors
associated with the poorer selectivity observed for this
Supporting Information Available. Information in-
1
cludes details of synthesis, H and 13C NMR spectra,
and mass spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 15, 2013
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