Convergent synthesis of polynitrile and/or polyamine dendrimers through hydroaminomethylation and Michael addition

Article abstract of DOI:10.1002/ejoc.201001307

A general concept for a versatile convergent synthesis ofpolynitrile and/or polyamine dendrimers has been developed by applying Voegtle's procedure in combination with thetandem hydroformylation/reductive amination sequence, known as hydroaminomethylation

Full text of DOI:10.1002/ejoc.201001307

FULL PAPER
DOI: 10.1002/ejoc.201001307
Convergent Synthesis of Polynitrile and/or Polyamine Dendrimers through
Hydroaminomethylation and Michael Addition
Maryam Beigi,[a] Stefan Ricken,[a] Kai Sven Müller,[a] Fikret Koç,[a] and Peter Eilbracht*[a]
Keywords: Dendrimers / Hydroaminomethylation / Hydroformylation / Michael addition / Homogeneous catalysis
A general concept for a versatile convergent synthesis of
polynitrile and/or polyamine dendrimers has been developed
by applying Vögtle’s procedure in combination with the
tandem hydroformylation/reductive amination sequence,
known as hydroaminomethylation. In this approach, first
Vögtle’s procedure is used to generate the desired dendron,
which can then be attached to different types of polyfunc-
tionalized cores (e.g., polyamine, polyhalide, or polyolefin
cores) to provide the desired globular architecture. This
method can be used as a general procedure for the synthesis
of dendrimers with designed shell and core properties as
shown by the examples presented.
solid-phase supports.[16] They have also been found to be
useful building blocks and carrier molecules that operate at
nanoscales.[18]
Introduction
Hydroaminomethylation[1] is an environmentally benign
and atom-efficient rhodium-catalyzed one-pot reaction that
combines hydroformylation of olefins[2] with reductive
amination[3] of the corresponding aldehydes in the presence
of an amine (Figure 1).
Convergent[19] and divergent[20] methods are two comple-
mentary approaches that are used to synthesize highly sym-
metrical dendrimers with defined properties depending on
their core and shell structure. Vögtle et al. developed early
examples of a successful divergent synthetic procedure[21]
toward the formation of well-defined, branched polyamine
dendrimers. The sequence starts from a polyamine, which
serves as the core of the final dendrimer. The growth of the
amine core proceeds outward by repetitive application of a
coupling reaction (Michael-type addition with acrylonitrile)
followed by an activation step (reduction with CoCl2 and
NaBH4) to provide primary amines in high yields.[22] Ac-
cording to this procedure, several commercial applications,
such as the bulk production of poly(propylene imine) (PPI)
type dendrimers (based on diaminobutane), have been de-
veloped.[23]
Figure 1. Hydroaminomethylation reaction.
This method has already been used in the synthesis of
linear and cyclic polyfunctionalized amines including poly-
amines and azamacroheterocycles.[4] Moreover, application
of this method has been proven in the synthesis of dendritic
structures as well as in their modification, offering versatile
access to new features of dendrimers.[5]
The interest in dendrimers,[6] which are – ideally – perfect
monodisperse macromolecules with a regular three-dimen-
sional architecture, has grown exponentially over the last
two decades. Due to the highly branched globular structure
of dendrimers, they are attractive scaffolds for a wide vari-
ety of high-end applications, such as liquid crystals,[7] diag-
nostics,[8] solar cells,[9] sensors,[10] gene-transfection
agents,[11] drug-delivery systems,[12] coating agents,[13] addi-
tives in commodity plastics,[14] and potential drugs.[15]
Moreover, they have been successfully employed in a wide
variety of catalytic reactions[17] as alternatives to insoluble
However, Vögtle’s method, which is generally used in a
divergent approach, has some limitations when proceeding
to higher generations of dendrimers. In these cases, a de-
crease in the solubility of the polynitriles, incomplete re-
duction, and also deficient functionalization due to reverse
Michael addition are observed. As an alternative, we envi-
sioned a convergent approach by applying Vögtle’s pro-
cedure for the construction of individual dendrons, with the
final assembly of the polyamine/polynitrile dendrimers be-
ing achieved by other synthetic methods, including hydro-
aminomethylation. By using this approach, the number of
functional groups on the dendron is much lower for each
step and generation. Furthermore, the critical reduction
step can be performed on the dendron before the complete
dendrimer is assembled. In addition, this approach seems
to be more flexible, because the preformed dendron could
be modified at the terminal function before being attached
[a] Organische Chemie, Technische Universität Dortmund,
Otto-Hahn-Str. 6, 44227 Dortmund, Germany
Fax: +49-231-755-5363
E-mail: peter.eilbracht@udo.edu-mail
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001307 or from
the author.
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Synthesis of Polynitrile and/or Polyamine Dendrimers
Scheme 1. Strategies for convergent syntheses of polynitrile/polyamine dendrimers.
to a suitably polyfunctionalized core to provide a globular
Results and Discussion
architecture with designed core and shell properties.[18]
Thus, we hoped to circumvent the disadvantages of the di-
vergent method.
Dendron Preparation
As shown in Scheme 1, the choice of the core and the
The construction of various dendrons was accomplished
reaction type used in the final step in the convergent ap- by repetitive Michael additions of acrylonitrile to an N-pro-
proach is more flexible and even allows the use of small tected primary amine, followed by reduction of the nitrile
dendrimers as core molecules. When hydroaminomethyl- groups (Table 1).[21] The sequence was optimized by using
ation is used as the assembly method, attachment of the water as the solvent for the addition step, and Raney-Co
dendrons to the core should be conveniently achieved by was utilized as the catalyst for the reduction of the nitrile
allylation of the deprotected amine function at the focal groups.
point of the dendron, followed by hydroaminomethylation
To determine the most suitable protecting group (PG) at
in the presence of a polyamine core (Scheme 1, Method A). the focal point of the dendron, different amine protecting
In principle, this pathway can also be reversed by allyl- functionalities were screened (Table 1, Entries 1–5). All the
ating the polyamine core to obtain a polyolefin core, which starting materials studied gave reasonable results, and the
can then be converted into the desired dendrimer through final nitrile dendrons (second generation) (3a–g) were ob-
hydroaminomethylation with the preformed free N–H tained in 70–100% yield, depending on the protecting
group at the focal point of the dendron (Scheme 1, group. As shown in Table 1 (Entries 6 and 7), instead of
Method B). Alternatively, the allylation/hydroaminomethyl- protected amines, amino alcohols can also be attached to
ation strategies (Scheme 1, Methods A and B) can be re- the dendron.[24] The corresponding functionalities offer the
placed by other reaction types, such as alkylation or acyl- advantage that only the NH2 groups act as nucleophiles in
ation of the dendron by using a polyhalide core (Scheme 1, the Michael-type addition with acrylonitrile, whereas the
Method C). As shown in Scheme 1 for the first dendrimer free OH group remains available either for final couplings
generation, this procedure can, in principle, also be further to the core or for further modification of the dendron.
applied to higher generation dendrons and/or higher gener-
ation cores.
In principle, the e series of dendrons, with an additional
carbon atom in the chain, can also be constructed by a
We herein present the first application of this convergent hydroformylation/reductive amination sequence by using
approach to the preparation of polynitrile/polyamine den- the N-allylated dinitrile 4 followed by reduction to give 7
drimers according to the strategy depicted in Scheme 1. The (Scheme 2).
method was used to combine Vögtle’s procedure either with
allylation/hydroaminomethylation or alkylation/acylation propionitrile (4) was hydroformylated to form aldehyde 5
to demonstrate the effectiveness of the new pathway.
by using [Rh(acac)(CO)2] as the catalyst[28] and 4,5-bis(di-
According to this approach, first, 3,3Ј-(allylimino)di-
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Table 1. Preparation of various N-protected dendrons according to groups, which may deactivate the catalysts by complete ab-
Vögtle’s method.
sorption onto its surface. In this case, the palladium surface
will not be accessible for the benzyl group, which is a pre-
requisite for deprotection. Nevertheless, reduction of the ni-
trile groups was not observed here.
As an alternative, debenzylation succeeded when a spe-
cial Pd/C catalyst (wet, Degussa type E101 NE/W, Aldrich
33,010-8) was used to form product 8 from 3a, but only
after extended reaction time (14 d) (Table 2, Entry 1). This
long reaction time and the poor yield once again indicated
that strong deactivation of the palladium catalyst by the
polynitrile groups was taking place.
Table 2. Deprotection of the dendrons 3a–d.
[a] Compound 1e was prepared in four steps by starting from piper-
azine: (1) mono-Boc-protection of piperazine[25] (80% yield), (2)
Michael addition to acrylonitrile[26] (94% yield), (3) reduction of
the nitrile group[27] (100% yield), (4) Michael addition to acryloni-
Deprotection and activation of the p-methoxybenzyl-
trile (92% yield). [b] Compound 1g was prepared from 1-[2-(2-
(PMB-)amine-functionalized dendrons (b series), can be
achieved either by debenzylation, as stated above, or by de-
protection of the p-methoxy group, which leads to a phenol
derivative. Debenzylation of 3b is known to proceed
hydroxyethoxy)ethyl]piperazine by Michael addition and reduction,
in an overall yield of 85%.
phenylphosphanyl)-9,9-dimethylxanthene (XANTPHOS)[29] through either reduction or oxidation; however, neither re-
as phosphane ligand, which directed the reaction toward ductive debenzylation by using Pd/C as the catalyst, nor
selective formation of the linear aldehyde (linear/branched, oxidative debenzylation by using 2,3-dichloro-5,6-dicyano-
13:1). Subsequent reductive amination with Boc-piperazine 1,4-benzoquinone (DDQ) or CeIV ammonium nitrate, were
provided the corresponding polynitrile 6. Finally, reduction successful in this case. Similarly, demethylation of 3b with
[32]
of the nitrile groups of 6 led to the formation of 7 in quanti- BBr3
did not provide the desired phenol product
tative yield.
(Table 2, Entry 3).
For final attachment of the thus obtained dendrons to
For deprotection of the Moc group, harsh conditions
an appropriate core, a suitable deprotection protocol was were required, which led to decomposition of the nitrile
required. Therefore, in the next step, deprotection of the functionalities, as well as the starting material in the case
amino protecting groups of the tetranitriles (Table 1, 3a–e) of 3d (Table 2, Entry 5).
was tested. Debenzylation of 3a by using various reagents,
The best result was obtained for deprotection of the Boc
such as Pd/C/ammonium formate,[30] Pearlman’s catalyst group of 3c, where reasonable yields were achieved when
[Pd(OH)2/C, H2],[31] or Pd/C and H2, failed. This lack of the reaction was carried out with HCl in dioxane (Table 2,
success could be attributed to the presence of the nitrile Entry 4).
Scheme 2. Dendron synthesis by a hydroformylation/reductive amination/reduction sequence.
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Synthesis of Polynitrile and/or Polyamine Dendrimers
In case of the e series, with compounds starting from
To emphasize the generality of this method, different
tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate, Boc kinds of star-shaped cores [e.g., polyamine (Method A),
deprotection was even more efficient. The corresponding polyolefin (Method B), and polyhalide (Method C)
deprotected dendrons 9 and 10 could be synthesized in ex- (Scheme 1)] were considered for attachment to the corre-
cellent yields (Table 3) under the same conditions used sponding dendron. Detailed results are discussed in the fol-
above (Table 2, Entry 4). This significant improvement in lowing sections.
yield might be attributed to the presence of an alkyl spacer
in the e series, which makes the protected amine more ac-
Attachment of Dendrons to a Polyamine Core (Method A)
cessible to the catalyst.
To attach an amine-functionalized dendron to a poly-
amine core, an olefinic chain was introduced at the focal
point of the dendron by N-allylation. The allylated dendron
could be attached to the amine core through hydroamino-
methylation. To circumvent the selectivity problem in hy-
droformylation of allyl groups, first the methallyl group was
introduced by using methallyl chloride as the N-alkylating
agent. The results of hydroaminomethylation of methallyl-
modified dendrons 11 and 12 with 1,3,5-tris(piperazino-
Table 3. Boc deprotection of e-series dendrons.
Table 4. Hydroaminomethylation of modified olefinic dendrons
with polyamine core 13.
In conclusion, the Boc functionality was chosen as the
most appropriate protecting group for further experiments.
Attachment of the Dendrons to a Core
As discussed above (Scheme 1), the idea of the new strat-
egy was to apply Vögtle’s procedure in combination with
hydroaminomethylation to construct the desired polyamine/
polynitrile dendrimers through a convergent approach.
Therefore, having prepared the model dendrons through
Vögtle’s procedure, the dendrons needed to be attached to
a suitably polyfunctionalized core to provide the desired
globular architecture (Scheme 1).
Scheme 3. Hydroaminomethylation of 11 with the tris(primary amine) core 16.
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methyl)benzene (13) as a triamine core with secondary yield with
a
molecular weight above 1300 gmol–1
amino groups, are shown in Table 4.
(Scheme 3).
The corresponding dendrimers 14 and 15 with molecular
Instead of using polynitrile-terminated dendrons, as an
weights higher than 1000 gmol–1 were purified by dialysis alternative the nitrile groups can be reduced and further
and could be isolated in 60 and 43% yields, respectively modified at the amine functions prior to assembling the
(Table 4).[33]
dendrimer. Thus, the terminal amine groups in dendron 2e
The triamine core 16, with primary amino groups, was were modified with decanoyl chloride to form 18 followed
then tested for rapid assembly of dendrimers. This core was by deprotection to provide 19. Allylation of 19 with methal-
prepared in two steps from ammonium acetate and acrylo- lyl chloride delivered 20 as the desired dendron. Hydroami-
nitrile followed by reduction with Raney cobalt.[34] Poly- nomethylation of 20 with the triamine core 13 was success-
amine 16 underwent a six-fold hydroaminomethylation with fully accomplished to give the hexadecanoate dendrimer 21
dendron 11 to generate in one step dendrimer 17 in 60% in 21% yield (Scheme 4). Dendrimers with structural prop-
Scheme 4. Modification of dendron 2e with decanoyl chloride, olefinic functionalization, and hydroaminomethylation to the hexadecan-
oate dendrimer 21.
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Synthesis of Polynitrile and/or Polyamine Dendrimers
erties typified by compound 21, bearing a basic polar core
and a hydrophobic shell, have potential applications as sup-
ramolecular hosts for encapsulating polar guest mole-
cules.[35]
Attachment of Dendrons to a Polyolefin Core (Method B)
As an alternative to Method A, hydroaminomethylation
can also be applied to polyolefin cores by using dendrons
with free N–H groups at the focal point. As a first example
of this version, hydroaminomethylation of the commercially
available triolefinic core, tris(2-methylallyl)amine (22), with
amine-functionalized dendron 8 was investigated under dif-
ferent conditions (temperature, pressure, and time). This ap-
proach, however, was unsuccessful.
Scheme 5. Stepwise hydroformylation and reductive amination of
tris(2-methylallyl)amine (22).
1,2-diamine (24) in 60% yield. Here again, direct hydroami-
When the reaction was performed in a stepwise manner nomethylation of 24 failed, and in the stepwise version, al-
by hydroformylation and subsequent reductive amination, though polyaldehyde 25 could be detected in the reaction
tris(aldehyde) 23 was obtained in quantitative yield; how- mixture, due to its instability it could neither be isolated in
ever, reductive amination in the second step failed, due to pure form nor converted into the desired product 26
polycondensation of the polyaldehyde after addition of the through reductive amination (Scheme 6).
polyamine/polynitrile dendron 8 (Scheme 5).
As shown by these results, Method B is clearly less favor-
As discussed above, polyolefin cores can also be obtained able than Method A due to the local concentration of alde-
by perallylation of polyamine cores. Thus, allylation of hyde groups in close vicinity and, consequently, side reac-
tris(2-aminoethyl)amine with triethylamine in toluene tions that cannot be avoided by higher dilution. Therefore,
provided N,N-diallyl-NЈ,NЈ-bis[2-(diallylamino)ethyl]ethane- polyolefin cores needed to be designed with larger spacers
Scheme 6. Stepwise hydroaminomethylation of N,N-diallyl-NЈ,NЈ-bis[2-(diallylamino)ethyl]ethane-1,2-diamine (24).
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Scheme 7. Hydroaminomethylation of 27.
that separate the olefin and aldehyde functions further. To tection step. Conversion with the tris(carbonyl chloride)
test this hypothesis, the olefinic core 27 was prepared by core 32 furnished the respective polyamine dendrimers 33
allylation of 1,3,5-tris-(piperazinomethyl)benzene (13) in and 34 in excellent yields (Scheme 9). Similarly, amine-func-
65% yield. As expected, hydroaminomethylation of 27 with tionalized dendron 10 reacted with the tris(carbonyl chlo-
3-{(2-cyanoethyl)[3-(piperazin-1-yl)propyl]amino}propio- ride) core 32 to provide 35 in high yield.
nitrile (9) as the dendron succeeded, and 28 was generated
in 57% yield (Scheme 7).
Conclusions
Attachment of Dendrons to Halogenated Cores (Method C)
As discussed above, another alternative for the construc-
We have expanded a general concept for the flexible syn-
tion of polynitrile/polyamine dendrimers is offered by alk- thesis of polyamine dendrimers starting with highly versa-
ylation or acylation of dendrons such as 8, 9, or 10 with tile dendrons obtained by Vögtle’s method. These dendrons
free N–H groups at the focal point with appropriately func- can be combined with suitable cores in various ways, thus
tionalized cores. As an example, nucleophilic substitution providing a powerful and versatile toolbox for the rapid as-
reaction of 1,3,5-tris(bromomethyl)benzene (29) with the sembly of dendrimers with any desired molecular weight in
amine-functionalized dendron 10 provided dodecanitrile 30 only a very few steps by coupling individually designed
in one step with 42% yield. This polynitrile could be sub- cores, dendrons, and shells. According to our results,
sequently reduced to form dodecaamine 31 in 46% yield Method B was found to be less favorable than Methods A
(Scheme 8).
and C, due to the high local concentration of aldehyde
Another strategy was to apply dendrons with the free groups, which leads to side reactions that cannot be over-
OH groups at the focal point, which can be attached to come by higher dilution.
tricarboxylic chloride core 32 as reported by Tschierske et
To the best of our knowledge, this is the first time that
al.[36] Appropriate amino alcohol dendrons, such as 1f or dendrons of this type (prepared according to Vögtle’s pro-
3f, are conveniently constructed without requiring any pro- cedure) have been used in a convergent manner.
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Synthesis of Polynitrile and/or Polyamine Dendrimers
Scheme 8. Synthesis of polyamine dendrimer 31 by nucleophilic substitution/reduction.
as films on NaCl or KBr plates with a Nicolet Impact 400D FTIR
spectrometer. High-resolution mass analyses were performed with
a Jeol JMS-SX 102A instrument operating at 70 eV.
Experimental Section
General Experimental Details: All reagents and solvents were puri-
fied or dried before use by the usual procedures. [Rh(cod)Cl]2 was
General Procedure for the Michael Addition of Acrylonitrile to
Amines (GP1): The amine (1.0 equiv.) was dissolved in water, and
acrylonitrile (2.5 equiv. per amine group) was added dropwise. The
mixture was heated to reflux for 2–3 h (for amino alcohols at room
temperature for 3 d). The excess acrylonitrile was evaporated under
vacuum, and the oily residue was mixed with chloroform and added
to water. The organic layer was washed with water (ϫ2) and dried
with MgSO4. Filtration and evaporation of the solvent afforded the
product.
prepared according to
a
literature procedure.[36] Column
chromatography was carried out on 70–230 mesh silica gel (Mach-
erey-Nagel; silica gel 60). Dialysis was performed by using benzoyl-
ated cellulose tubing (Sigma–Aldrich, MWCO 1000) with chloro-
form, dichloromethane, or methanol as the solvent. High-pressure
reactions were carried out in a magnetically stirred Berghof type A
(250 mL, four glass vials, each 20 mL) pressure vessel, a similar in-
house made autoclave (100 mL), or in a PARR autoclave. 1H NMR
spectra were recorded with a Bruker Avance DRX 400 or Bruker
Avance DRX 500 spectrometer. Chemical shifts (δ) are reported in
ppm relative to TMS, with CDCl3 (δH= 7.24 ppm, δC = 77.0 ppm)
or CD3OD (δH = 3.30 ppm, δC = 49.0 ppm) as internal standard.
Coupling constants (J) are given in Hz. IR spectra were recorded
General Procedure for the Reduction of Polynitriles (GP2): The ni-
trile compound (100 wt.-%) was dissolved in a small amount of
methanol in a PARR autoclave. Water (100 mL) was added to gen-
erate a milky suspension. Raney cobalt catalyst (200 wt.-%; wet;
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Scheme 9. Synthesis of polynitrile dendrimers by reaction with an acyl chloride core.
type Grace 2724 from Grace; manufacturer’s specification: 78–
96 wt.-% Co, 0.5–5 wt.-% Ni, 0.5–5 wt.-% Cr, 3–12 wt.-% Al) was
washed with water and introduced into the autoclave. After the
autoclave had been closed, stirring of the mixture was started, and
the autoclave was purged twice with Ar and once with H2. The
autoclave was heated to 65–75 °C while stirring (1500 rpm) at a H2
pressure of 30–50 bar. The reaction was carried out under H2 for
2 h to 1 d and stopped by cooling of the autoclave to room tem-
perature. The H2 was drained, and the autoclave was purged with
Ar, opened, and the contents were immediately filtered. Solvent
evaporation afforded the desired product.
room temperature overnight. The solvent was removed, and sodium
hydroxide was added until a strongly basic solution was obtained;
then the solution was extracted immediately with dichloromethane
(ϫ3). The organic layer was dried with MgSO4, and the solvent
was removed under reduced pressure.
General Procedure for the Hydroaminomethylation Reaction (GP4):
The olefinic compound (1 equiv. for every secondary amine group,
2 equiv. for every primary amine group), [Rh(acac)(CO)2] (1 mol-
%), and the amine (core) were dissolved in a solvent mixture (usu-
ally dioxane/methanol/triethylamine), placed in an autoclave, and
pressurized with 40 bar H2 and 40 bar CO. After stirring at 80–
120 °C for 2–3 d, the solvent was removed, and the crude product
was purified by dialysis and analyzed by NMR spectroscopy.
General Procedure for the Boc Deprotection (GP3): The Boc-pro-
tected amine was dissolved in dioxane/HCl (3 m; 3:2) and stirred at
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Acknowledgments
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