Identification of diamine linkers with differing reactivity and their application in the synthesis of melamine dendrimers

Article abstract of DOI:10.1016/j.tetlet.2007.12.056

Diamine linkers for the synthesis of dendrimers based on melamine were identified using competition reactions. The relative reactivity of the surveyed cyclic monoamines varies by 40 times, expanding the previously identified series to an overall relative reactivity range of 320 times. Azetidine is 40 times more reactive than the cyclic, nine-membered ring (C₈H₁₇N), and 320 times more reactive than benzylamine. Reactivity differences are attributed to pK_a values and sterics. Diamines incorporating these groups are useful linkers that can be employed in dendrimer synthesis. Specifically, the nucleophilicity of the individual amine groups comprising 3-aminoazetidine, 3-aminopyrrolidine, and 4-aminopiperidine varies by 100 times, 70 times, and 20 times, respectively. These linkers are incorporated into a generation three dendrimer.

Full text of DOI:10.1016/j.tetlet.2007.12.056

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Tetrahedron Letters 49 (2008) 1152–1154
Identification of diamine linkers with differing reactivity and
their application in the synthesis of melamine dendrimers
Karlos X. Moreno, Eric E. Simanek *
Department of Chemistry, Texas A&M University, MS 3255, College Station, TX 77843, United States
Received 29 November 2007; accepted 11 December 2007
Available online 8 January 2008
Abstract
Diamine linkers for the synthesis of dendrimers based on melamine were identified using competition reactions. The relative reactivity
of the surveyed cyclic monoamines varies by 40 times, expanding the previously identified series to an overall relative reactivity range of
320 times. Azetidine is 40 times more reactive than the cyclic, nine-membered ring (C8H17N), and 320 times more reactive than benzyl-
amine. Reactivity differences are attributed to pKa values and sterics. Diamines incorporating these groups are useful linkers that can be
employed in dendrimer synthesis. Specifically, the nucleophilicity of the individual amine groups comprising 3-aminoazetidine, 3-amino-
pyrrolidine, and 4-aminopiperidine varies by 100 times, 70 times, and 20 times, respectively. These linkers are incorporated into a gen-
eration three dendrimer.
Ó 2008 Elsevier Ltd. All rights reserved.
Our group has invested significant energies in the syn-
thesis of dendrimers based on triazines, also referred to
as dendrimers based on melamine deriving from our use
of diamine linkers.1,2 Our early targets commonly incorpo-
rated p-aminobenzylamine because of the significant differ-
ences in the reactivity of the amines of this group. That is,
during a convergent synthesis, protecting group manipula-
tions and functional group interconversions could be
avoided because the benzylic amine would react preferen-
tially (essentially exclusively) with the monochlorotriazine
dendron being elaborated.1,3–7 The low stability of these
aniline derivatives required reasonable, but additional, care
on handling. While the use of distilled solvents and inert
atmospheres is uncommon, nor is the requirement for
refrigerated storage of intermediates, we recognized that
these precautions could impact the broader acceptance of
these materials.
However, when using piperazine, dimerization of mono-
chlorotriazines was observed under non-ideal reaction con-
ditions that were usually attributed to concentration, rate
of addition, ineffective stirring or lack thereof, temperature
of addition and the magnitude of stoichiometric excess.4,8–18
Reactions with either p-aminobenzylamine or piperazine
could be readily followed by NMR. The shift of the
benzylic protons on reaction with the monochlorotriazine
dendron or the desymmetrization of methylene groups of
the piperazine group was diagnostic. Unfortunately, detect-
ing dimeric sideproducts by NMR proves difficult due to
signal degeneracy between the desired asymmetric mono-
amine and the symmetric dimer.
The wealth of commercially available diamines led us to
conduct a rational survey of reactivity. Our goal was to
identify diamine linkers with the reactivity differences dis-
played in p-aminobenzylamine without the disadvantages
previously described. Our original study examined a range
of primary and secondary amines including the cyclic
amines piperidine and two piperazine derivatives (A–F,
Fig. 1).1 From these studies, aminomethylpiperidine
emerged as a diamine linker of choice and was used exten-
sively.1,2,7,9,15–17,19,20 Using competition experiments, the
The low cost and high reactivity of piperazine soon
made it a linking diamine of choice for our investigations.
*
Corresponding author. Tel.: +1 979 845 4242; fax: +1 979 845 9452.
E-mail address: Simanek@mail.chem.tamu.edu (E. E. Simanek).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.056

K. X. Moreno, E. E. Simanek / Tetrahedron Letters 49 (2008) 1152–1154
1153
Scheme 1. Three new diamine linker with the relative reactivity difference
of the diamines indicated.
should be commercially available or accessible in a minimal
number of steps. Diamine linkers L1–L3 (Scheme 1) were
chosen because they meet the criteria and are commercially
available. A single enantiomer of 3-aminopyrrolidine is
commercially available. These linkers were then evaluated
by preparing dendrimer 1 as a proof-of-concept.
Scheme 2 shows the convergent strategy used to synthe-
size dendrimer 1. Following selective protection of the
primary amines of 3,30-diaminodipropylamine with BOC–
Fig. 1. Relative reactivity map for the substitution of monochlorotria-
zines. The reactivity difference between consecutive amines is shown on the
scale.
relative reactivity difference measured for the cyclic second-
ary amine and primary amine of aminomethylpiperidine is
ꢀ20 times. Theoretically, 5% of the product formed might
derive from the reaction of the monochlorotriazine den-
dron with the primary amine instead of the desired second-
ary amine. This population difference approaches the limit
of detection by NMR spectroscopy, and accordingly the
efforts described here were undertaken to identify other
suitable diamine linkers. These amines are identified as
G–K in Figure 1.
To establish relative reactivity of different monoamines,
reactions were conducted by treating 1 equiv of a mono-
chlorotriazine, DMTA, with 3 equiv of two competing
amines chosen from G–K at room temperature (Supple-
mentary data). The reactivity map was obtained by deter-
mining the product ratios using 1H NMR after the
disappearance of DMTA. These values for individual com-
petition studies are consistent multiplicatively across the
range of amines within experimental error. Protons a to
the amine generally appeared downfield from those of the
free amines, and provided convenient signals for measuring
product distributions. Inclusion of A and F allows us to
compare this new series to the existing series.
Scheme 2. Synthesis of G3 dendron 6. Reagents and conditions: (a) THF,
rt, overnight; (b) THF, cyanuric chloride, Hunig’s base (DIPEA), 40 °C,
overnight; (c) THF, rt, overnight; (d) THF, cyanuric chloride, Hunig’s
base (DIPEA), 40 °C, 2d.
The data show that as the ring size decreases, the reactiv-
ity of the amine increases.21 The pKa of the conjugate acids
of most reactive amines (G, H, and A) is 11.3, while the pKa
of the conjugate acids of less reactive amines (I–K) is
10.8.22,23 Sterics can be used to rationalize the difference
in reactivity within these subgroups.
From these data, we identified new diamine linkers
based on three criteria. First, a minimum reactivity differ-
ence of ꢀ20 times between the amines should reduce dimer
Scheme 3. Synthesis of the core, 8. Reagents and conditions: (a) THF,
cyanuric chloride, Hunig’s base (DIPEA), 70 °C, 7d; (b) (1:1) TFA/DCM,
rt, overnight.
1
formation. Second, one or more unique H NMR signals
should facilitate characterization. Third, the diamine

1154
K. X. Moreno, E. E. Simanek / Tetrahedron Letters 49 (2008) 1152–1154
N R'
HN
N
N
N
HN
N
R
N
N
NHBoc
NHBoc
N R'
R =
N
HN
N
N
N
N
N
HN
N
a
HN
N
N
6 + 8
HN
N
(36%)
N
N
N
N
N
N
HN
R' =
NHBoc
NHBoc
NH
1
HN
RN
N
R'
Scheme 4. Synthesis of 1. Reagents and conditions: (a) THF, BEMP resin, 70 °C, 7d.
ON, treatment with cyanuric chloride affords monochloro-
triazine 2. Intermediate 2 is treated with an excess of L1 to
produce 3. In an iterative fashion, the synthesis continues
with the reaction of cyanuric chloride to form 4, then L2
to generate 5. Cyanuric chloride treated with a slight excess
of 5 gives 6. While iteration with 3-aminoazetidine pro-
gresses the sequence, sterics precludes trimerization with a
cyanuric chloride core.
Instead, a less sterically encumbered core, 8, is synthe-
sized by treating cyanuric chloride with L3 followed by
deprotection (Scheme 3). This strategy affords a highly
reactive core possessing three azetidine groups, which upon
reaction with a large excess of 6 (Scheme 4). The reported
yield of 36% represents the amount of material obtained in
pure form after extensive chromatography, and is not a
reflection of an unsuccessful reaction. Indeed, we estimate
conversion to product occurred in >80%.
References and notes
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In conclusion, we foresee that each linker offers interest-
ing features that could be exploited in future work. Amino-
azetidine (L1) offers a highly reactive and sterically
unencumbered amine that might find use in situations
where piperidine-type amines are unreactive or react slug-
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Acknowledgments
This work was supported by the National Institutes of
Health (NIGMS 65460). K.X.M. thanks the National Sci-
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NSF GK-12 program.
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2007.12.056.
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