Design, synthesis and structure of new dendritic melamines. First use of a tandem C-2-substituted serinol - O,O-masked 4-piperidone as a peripheral unit in iterative synthesis

Article abstract of DOI:10.1016/j.tet.2012.07.096

The iterative chemoselective amination of cyanuric chloride to dimers of new G-2 dendritic N-substituted-2,4,6-triamino-s-triazines (melamines) having C-2-substituted 2-aminopropane-1,3-diols ('serinols') in tandem with the ethylene ketal of 4-piperidone as peripheral units is reported. The structure as a function of increasing molecular size was studied by NMR spectroscopy, DFT calculation and AFM imaging. A concise nomenclature defining the restricted rotational phenomena about the newly created C(s-triazine)-N(exocyclic) partial double bonds, seen as axes of (pro)diastereomerism, is used. We propose a new form of frontier rotamerism for the dendrimer surface, which operates over a long range.

Full text of DOI:10.1016/j.tet.2012.07.096

Tetrahedron 68 (2012) 8945e8967
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Design, synthesis and structure of new dendritic melamines. First use of a tandem
C-2-substituted serinoldO,O-masked 4-piperidone as a peripheral unit in
iterative synthesis
Flavia Popa a , Pedro Lameiras , Oana Moldovan , Maria Tomoaia-Cotisel , Eric Henon ,
,
b
c
a
,
b
a
c
c
a
a
b
a,
*
Agathe Martinez , Carmen Sacalis , Aurora Mocanu , Yvan Ramondenc , Mircea Darabantu
Babes-Bolyai” University, Department of Chemistry, 11 Arany J aꢀ nos st., 400 028 Cluj-Napoca, Romania
University and INSA of Rouen, IRCOFdLCOFH, UMR 6014 CNRS COBRA, 76821 Mont Saint-Aignan Cedex, France
University of Reims Champagne-Ardenne, ICMR-LIS, UMR 6229, BP 1039, 51687 Reims, France
a
“
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
The iterative chemoselective amination of cyanuric chloride to dimers of new G-2 dendritic N-
substituted-2,4,6-triamino-s-triazines (melamines) having C-2-substituted 2-aminopropane-1,3-diols
Received 9 October 2011
Received in revised form 27 June 2012
Accepted 31 July 2012
(
‘serinols’) in tandem with the ethylene ketal of 4-piperidone as peripheral units is reported. The
structure as a function of increasing molecular size was studied by NMR spectroscopy, DFT calculation
and AFM imaging. A concise nomenclature defining the restricted rotational phenomena about the newly
created C(s-triazine)eN(exocyclic) partial double bonds, seen as axes of (pro)diastereomerism, is used.
We propose a new form of frontier rotamerism for the dendrimer surface, which operates over a long
range.
Available online 5 August 2012
Keywords:
Dendrimers
Melamines
Serinols
Ó 2012 Elsevier Ltd. All rights reserved.
4-Piperidone
NMR
AFM (atomic force microscopy)
1. Introduction
Resulting from pharmaceutical chemistry, Serinol is the trivial
nomenclature of 2-aminopropane-1,3-diol, seen as the reduced
form of Serine and the parent term for a series of compounds
comprising its commercial C-2-substituted analogues AeC
l
Chart 1).1
,y
(
2
It was in 1985 when Newkome et al. used TRIS (C) in the syn-
thesis of the first so-called ‘arborol’ that the chemistry of den-
drimers came about. Subsequent developments of these ‘cascade
3
syntheses’ suggested that TRIS could be a very attractive serinolic
building-block for dendritic structures. It could, for example, play
several roles within such structures: peripheral unit, tetravalent
branch cell and core.2b Both Serinol itself, as well as its cyclic acetals,
Chart 1. The C-2-substituted serinols’ family.
4
aef
proved of interest in the fields of biomedicine
and nano-
attention, however, has been hitherto paid to Methylserinol A and
Ethylserinol B.
materials4
g,h
for dendritic constructions of macromolecules. No
The last decade has seen much development in the field of
melamine-based dendrimers. This has flowed from the first results
5
a
of Simanek et al., in 2000. There have been various approaches to
this new class of macromolecule taken. First, in the domain of
*
Corresponding author. Tel.: þ40 264 59 38 33; fax: þ40 264 59 08 18; e-mail
5
aef
5a,gem
iterative convergent
versus divergent syntheses,
one
addresses: darab@chem.ubbcluj.ro, darabantu@cluj.astral.ro (M. Darabantu).
y
such approach consisted in the adding the ‘classic’ (but still useful)
The C-1-substituted serinols are also commercial as chiral (1S,2S)-‘phenylser-
inols’, e.g., R¼Ph or p-nitrophenyl.
chemoselective amination of cyanuric chloride. Not long after
0
040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.096

8946
F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
the publication of those results, Simanek et al. managed to
effect manipulations specifically relating to the peripheral
6
groups of dendritic melamines. In so doing, they highlighted two
7
major applications, organic nanomaterials and vehicles for drug
8
delivery systems. All this has been described several recent
reviews.9
The amination of cyanuric chloride with C-substituted
(
masked) serinols, such amination being combined with target-
ing bioactive N-substituted melamines, has, however, scarcely
10a,b
been touched since 1979.
Our group has previously reported
on the convergent synthesis of the first serinolic G-2 melamine
dendrimer incorporating (1S,2S)-p-nitrophenylserinol as pe-
ripheral units.1
1a,b
We also reported on our failure to arrive at
similar structures based on C-2-substituted serinols AeC (Chart
11b
1
).
In the course of our search for an additional challenging
amino-nucleophile (in tandem with serinols AeC in a new iter-
ative synthesis of melamines), we began to consider the ethyl-
12
ene ketal of piperidone. This compound is relevant
in
nucleophilic substitution of chlorine in certain chlorodiamino-s-
triazines, such substitution being carried out with 4-piperidone
derivatives. This provides pharmaceutical compositions for
treating pathological states that arise from, or are exacerbated
by, angiogenesis.12
Scheme 1.
So the aim of the present full report is to give an account of the
first melamine G-2 dimeric dendrimers (convergent synthesis,
structure and dynamic behaviour) that have the tandem C-2-
substituted serinoldO,O-masked 4-piperidone as peripheral
units. The compounds, to which the title of this paper refers,
combine, then, three ‘traditional’ biological units (serinols, s-tri-
azine and 4-piperidone) but in a dendritic context.
(ii) The opportunity to consider the new chlorodiamino-s-triazines
1a and 2a as simpler structures, i.e., ‘model compounds’, for
subsequent dendritic architectures that would incorporate these
motifs. We have previously discussed the relevance of this
11b
14
‘structuralsimulation’, around the same time as Simanek et al.
2.2. Synthesis of G-0 melamines. Selective installation of pe-
2
2
2
. Results and discussion
ripheral units and of the first linker
.1. Synthesis
Our first object of enquiry was the series of new melamines
6aee (Scheme 2, steps IeIII; Table 1).
.1.1. Preliminary inspection of reactivity of 4-piperidone and its
Initially, we followed three related lines of enquiry, series aec,
12
ethylene ketal with cyanuric chloride. As early as 1999, the se-
lective installation of a piperidine type motif as the first amino-
nucleophile on cyanuric chloride seemed to be not recom-
mended. Later on, Simanek’s convincing ‘relative reactivity
starting from serinols AeC in tandem with the ethylene ketal of
piperidone 2 (Scheme 1). Next, the optimised results (Table 1, entry
3 vs 2) encouraged us to consider two additional directions, d and e,
by including in our study the less polar 2-amino-2-methylpropanol
5
d,f,j
5i,h
15a
maps’
that focused on elaborating dendritic melamine
(D).
Just as had been the case with AeC, the role for D was as
confirmed this negative observation. Furthermore, the instability
a peripheral unit, whether in combination with 2 (series d), or
alone (series e). The opening step (amination I), performed with the
weaker amino-nucleophiles AeD, was routine (Table 1, entry 1),
with TLC monitoring indicating completion in all cases 3aed. By
contrast, in amination step II, the selective preparation of un-
of 4-piperidone free base with respect to autocondensation has
13a
been common knowledge since 1949. Therefore the use instead
of its stable hydrochloride derivatives, ‘monohydrate’ 1 or ethyl-
ene ketal 2 is suitable (Scheme 1). In the context of these prem-
11b,13bed
0
ises, we have previously reported
satisfactory results in
symmetrically N,N -substituted chlorodiamino-s-triazines 4aed
the syntheses shown in Scheme 1. Both salts, 1 and 2 (the latter
(Table 1, entry 2 vs 3) required (i) low temperature and (ii) slow
gradual addition of 2 to the reaction mixtures that contained the
non-isolated 3aed. Under these conditions, TLC control confirmed,
besides total consumption of these intermediates (Table 1, entry 3),
minimum incidence of side reactions, e.g., complete amination
(/melamines 5a, 5b, Table 1, entry 2) and possible contaminating
13e
freshly prepared, according to Bickelhaupt et al. ), exhibited
a notably reduced solubility in the anhydrous solvents that are
usually used for this chemistry (THF, 1,4-dioxane, chloroform and
dichloromethane). Combined with the insolubility of our in-
expensive proton scavenger (K CO ) in the same solvents, the
2 3
corresponding free bases were not quickly generated from 1 and 2.
By contrast, a rapid acidebase interchange between 1 or 2 and
16
hydroxylation and/or alkoxylation of 3aed.
0
The one-pot synthesis (steps IþII) of symmetrically N,N -
substituted chlorodiamino-s-triazine 4e (Table 1, entry 4) was
simple and clean, with good yield.
2 3
K CO occurred in 10% aq THF, and the in situ resulting amino-
nucleophiles showed high strength. Indeed, the displayed results
in the syntheses 1/1a and 2/2a were due to manipulations in
very mild conditions only. These conditions ensured complete
chemoselectivity for di- versus trisubstitution of chlorine in cya-
nuric chloride.
In step III, we effected, in accordance with our previously
published method, the selective anchorage of the first piperazine
11,13c
linker (Table 1, entry 5).
We detected symmetric double
melamines 7 as side products and isolated them using column
chromatography on partially deactivated silica gel (i-PrOH or
These preliminary data suggested to us our next steps:
3
EtOH/aq 25% NH 9:1) in only three cases, 7a, 7b and 7e. Our
(
i) Careful monitoring of 4-piperidone based nucleophilic species
when selective S 2Ar aminations are envisaged.
explanation for the observed chemoselectivity makes use of an
alternative synthesis (Scheme 2) of dimeric G-0 melamines 7a
N

F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
8947
H
N
NH
B
7
R7
R
N
Cl
N
T-1
N
A
T-1
N
N
N
N
N
N
7
= R7
NT-0
N
N
A
= R
N
A
IV
V
VI
9a or 9e
HN
R1
N
R3
N
N
R2
N T-0
N
N T-0
+
0.32 eq. C N Cl
3
3
3
OH
6a-e
R3
R3
1.00 eq. K CO
DMF, 0 - 100 C
2
3
HN
N
HN
N
Series a-d
o
R1
R1
R2
R2
O
O
3
1
0a (traces)
0e [70]
R = N
OH
OH
1
9
a (78); 9b (85);
Series e
3
9c (73); 9d (80); 9e (70)
R = NH-C(Me) CH OH
2
2
8
R
R8
8
8
R =
N
N
NT-2
N
R =
9
R =
T-2
N
N
Cl
N
N
N
B
B
R7
N
T-1
N
R7
N
T-1
N
9
VII
R
NH
N
N
N
N
N
=
R7
=
R7
HN
N
A
N
A
c
d
1
0a [73], (87)
0b [78], (91)
0c [56]
11a [46] , [90] ; 11b [68], [92]
11c [-], [88]; 11d [48], [91]
N
N
1
1
1
1
NT-0N 11e [62], [83]
R3
N T-0
N
0d (98)
HN
R3
HN
N
0e [63], (70)
R1
R1
R2
R2
OH
OH
a
b
In square brackets: yield after isolation by column chromatography; In round brackets: yield after isolation by
c
d
direct crystallisation; In series 11: yields by neglecting the recovered as unreacted 10; Conversions of 10.
o
Key IV: i) 0.45 eq. C N Cl , 1.00 eq. K CO , THF, (-10 C) → r.t., 12 h.; ii) 1,4-dioxane, reflux: 11 h. (8a),
3
3
3
2
3
1
2 h. (8b), 16 h. (8c), 8 h. (8d), 11 h. (8e).
V: 4.00 eq. piperazine, 1.00 eq. K CO , 6 × 0.16 eq. 8a-e, THF, reflux, 6 × 1.5 h.
2
3
o
VI: i) 0.48 eq. C N Cl , 1.00 eq. K CO , THF. (-10 C) → r.t., 12 h., reflux, 16 h.; ii) 1,4-dioxane, reflux, 6 h.
3
3
3
2
3
o
VII: 0.48 eq. 4,4'-bipiperidine, 1.00 eq. K CO , DMF, 100 C, 36-72 h.
2
3
Scheme 2.
and 7e. The reaction between piperazine and 2.03 mol equiv of 4a
or 4e in the presence of K CO , needed 12 h in refluxing 1,4-
2.3. Synthesis of G-1, -2 dendritic melamines. Feasibilities and
failures
2
3
dioxane to yield 7a (87% yield) and 7e (76% yield). To explain
these results, we suggest that the transannular effect of pipera-
zine favours its mono-N-substitution. This effect was previously
noticed by Lai et al.7
Our next study involved the twofold anchorage of melamines
G-0 6aee (step IV, Scheme 3) to cyanuric chloride. From this we
produced G-1 chlorodendrons 8aee. As in step II, where the
e,f

8948
F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
Table 1
Results and conditions in the synthesis of compounds 4e7
Step
Entry
1
Molar ratios
Reaction conditions
THF, rt, 24 h
Main and by-products (yields, %)
I
1.00 AeD
3aed not isolated
3 3 3
1.00 C N Cl
1.00 K
2
CO
3
ꢀ
a
II
2
3
1.00 (2)
.00 K CO
THFþ10% H
(ii) /rt, 12 h
iii) rt, 24 h
2
O
(i) (ꢁ12 C), 12 h
4a [53] þ5a [4]
2
2
3
4b [58]þ5b [5]
4c (76)
(
b
ꢀ
b
5ꢂ0.20 (2)
.00 K CO
THFþ10% H
2
O
(i) (ꢁ12 C), 5ꢂ1.5 h
4a (83)
4b (87)
d (85)
2
2
3
(
ii) 36 h., (ꢁ15 C)
ꢀ
4
IþII
4
5
0.49C
.00 K
3
N
3
Cl
3
THF
4e (75)c
1
2
CO
3
(
i) (ꢁ10 C/rt), 12 h
ꢀ
(
ii) rt, 12 h
ꢀ
(
iii) 45 C, 13 h
III
4.00 piperazine
THF, rt, 6ꢂ1.5 h
6a [89]þ7a [6]
6
b [87]þ7b [1]
1.00 K
2
CO
3
6c (78)
6d (82)
6
ꢂ0.16 (4aee)
6e [85]þ7e [5]
a
In square brackets: for compounds 4a and 4b as partial conversions of cyanuric chloride into the depicted compounds; for compounds 6a, 6b and 6e as partial conversions
of their corresponding precursors, 4a, 4b and 4e.
b
Five equal portions of 2 (Scheme 1) each 1.5 h.
Our result; according to literature,
c
15a
no yield was reported for this compound but a general procedure published previously, in the period of 1950.15b
peripheral hydroxyl groups were unprotected, we began our ma-
nipulations at low temperature in THF, continued them at room
temperature and finished in refluxing 1,4-dioxane. The more taxing
conditions required for this step IV were justified on account of the
high solvation in THF and 1,4-dioxane of our nucleophiles 6aee. For
a satisfactory or good yield from this double amination, the process
required a 10% molar equivalent excess of 6aee/1 equiv chlorine in
cyanuric chloride.
because, given the failures mentioned above, we believed our
central linker should be larger. Therefore, since Simanek et al.
recently reported the use of 1,3-di(piperidin-4-yl)propane
5
k
(‘trimethylenedipiperidine’) in a protectiveedeprotective strategy,
0
we considered the use of 4,4 -bipiperidine. This diamine
(commercially available as dihydrochloride) has not hitherto been
the object of enquiry with respect to dendritic melamine chemistry.
Initial experiments revealed that (i) DMF was the most suitable
solvent in circumstances where the temperature did not exceed
It was, furthermore, equally necessary to adopt the more taxing
conditions of refluxing THF for step V, which involved the mono-
attachment of the second piperazine linker B to chlorodendons
ꢀ
0
100 C, (ii) the 4,4 -bipiperidine free base should be generated first
18
in a separate experiment and (iii) a 2:1.1 molar ratio of 10aee/4,
4 -bipiperidine worked best. MS spectra of the crude reaction mix-
0
8
aee. We followed an experimental protocol that was the same as
that adopted for step III (Scheme 2). No side-product dimeric G-1
melamines, analogues of G-0 7, were detected. Yields, however, of
melamines G-1 9aee when compared to those of melamines G-0
tures displayed, in accord with TLC, the same two types of compo-
nent in each case: the unreacted 10aee and desired 11aee. No
molecular peak consistent with the presence of a mono-N-
0
6
aee, were slightly smaller. Our tentative explanation relates to the
substituted-4,4 -bipieridine was detected.
higher relative retention on column chromatography.
Direct crystallisation as a separation technique was only feasible
in the case of mixture 10bþ11b when the yield (69%) was almost
the same as the yield achieved by column chromatography on silica
gel (68%). As the results demonstrated, in spite of some promising
conversions of dendrons 10aee, yields were affected, overall, by
retention of 11aee on silica gel. Except in the case of 11c, all den-
drimers provided credible analytical data (see Supplementary data
‘SD’ and Experimental section). The seven-step IeVII convergent
synthesis of G-2 dendritic melamines 11a, 11d and 11e produced
consistent global yields of 17e18%. However, starting from Ethyl-
serinol (B), the best result in the case of dendrimer 11b was 31%. The
explanation for this remains obscure.
Surprisingly, although the final installation of a trivalent s-tri-
azine core is commonly used in the synthesis of dendritic mela-
5
fek,7b,h,8b,c,e,f,14
mines,
the attempted triple amination of cyanuric
chloride with G-1 dendrons 9a and 9e was unsuccessful, pre-
17
sumably because of the ‘starburst effect’. Starting from 9a, de-
composition of the organic material occurred as both NMR and TLC
of the crude reaction mixture evidenced. In the mass spectrum
(
MALDIþ), we found that the molecular peak was only consistent
with formation of the G-2 chlorodendron 10a. Our treatment of
cyanuric chloride with 3.15 mol equiv of 9e was also disappointing
(Scheme 3), only producing chlorodendron G-2 10e.
From these failures, we took the view that it was best to avoid
Two additional negative results should also be mentioned:
similar experimental manipulations that would start from chlor-
odendrons 9bed. So we planned a series of experiments having
their origin in G-2 chlorodendrons 10aee, rather than looking for
a larger trivalent core. Applying a similar experimental procedure
for our next step (VI) to the one we applied in step IV (Scheme 2),
happily resulted in clean reactions and ready work-up.
(i) The failure to isolate compound 11c as a pure analytical sample.
The unreacted 10c was recovered easily by using CHCl
3
/MeOH/
Et
2
O 3.5:1.0:0.5 but eluting with CHCl /MeOH 3.5:1.0 to give 11c,
3
promoted its partial decomposition. Despite its credible MS anal-
ysis (see later on, Fig. VIc in SD 8), in the NMR spectra, including the
In the final step, (VII), we decided to couple two identical
building-blocks 10aee via a secondary diamine central linker. Pi-
perazine is repeatedly mentioned in the literature to play such
1
2D H DOSYexperiment,11c was the single macromolecular species
(Fig. VIId in SD 9), i.e., a component of a mixture of compounds with
lower molecular size.
5
aee,6aec,7a,7eeh
a role.
We were suspicious of the efficacy of this

F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
8949
H
N
NH
B
7
R7
R
N
Cl
N
T-1
N
A
T-1
N
N
N
N
N
N
7
= R7
NT-0
N
N
A
= R
N
A
IV
V
VI
9a or 9e
HN
R1
N
R3
N
N
R2
N T-0
N
N T-0
N
+
0.32 eq. C N Cl
3
3
3
OH
6a-e
R3
R3
1.00 eq. K CO
DMF, 0 - 100 C
HN
N
HN
2
3
Series a-d
o
R1
R1
R2
R2
O
O
3
R = N
1
0a (traces)
0e [70]
OH
OH
1
a
b
8
a [75] , (68) ; 8b (78);
9
a (78); 9b (85);
Series e
3
8c (86); 8d [68]; 8e (90)
9c (73); 9d (80); 9e (70)
R = NH-C(Me)2CH2OH
8
R
R8
8
R =
N
N
8
NT-2
N
R =
9
R =
T-2
N
N
Cl
N
N
N
B
B
R7
N
T-1
N
R7
N
T-1
N
9
VII
R
N
N
N
NH
N
N
= R7
HN
= R7
N
A
N
A
c
d
1
0a [73], (87)
0b [78], (91)
11a [46] , [90] ; 11b [68], [92]
11c [-], [88]; 11d [48], [91]
N
N
1
N T-0
N
10c [56]
NT-0N 11e [62], [83]
R3
1
0d (98)
HN
R3
HN
N
1
0e [63], (70)
R1
R1
R2
R2
OH
OH
a
b
In square brackets: yield after isolation by column chromatography; In round brackets: yield after isolation by
c
d
direct crystallisation; In series 11: yields by neglecting the recovered as unreacted 10; Conversions of 10.
o
Key IV: i) 0.45 eq. C3N3Cl3, 1.00 eq. K2CO3, THF, (-10 C) → r.t., 12 h.; ii) 1,4-dioxane, reflux: 11 h. (8a),
1
2 h. (8b), 16 h. (8c), 8 h. (8d), 11 h. (8e).
V: 4.00 eq. piperazine, 1.00 eq. K CO , 6 × 0.16 eq. 8a-e, THF, reflux, 6 × 1.5 h.
2
3
o
VI: i) 0.48 eq. C N Cl , 1.00 eq. K CO , THF. (-10 C) → r.t., 12 h., reflux, 16 h.; ii) 1,4-dioxane, reflux, 6 h.
3
3
3
2
3
o
VII: 0.48 eq. 4,4'-bipiperidine, 1.00 eq. K CO , DMF, 100 C, 36-72 h.
2
3
Scheme 3.
(
ii) The failure to deprotect the O,O-masked 4-piperidone
3. Structural investigations
peripheral units.
3.1. Analysis in solution by NMR techniques. Dynamic
Final N-, O- or S-deprotection of peripheral groups in dendritic
phenomena versus solvation effects
5
melamines is one of the strategies of choice in their synthesis. In
our case, however, all our attempts to apply to dendrimers 11a, 11b
and 11d the deprotecting protocol that had previously been re-
Asearlyas1971,19a itwasestablished that the C (s-triazine)eNsp3
sp2
19,20
connectionshave a partial doublebondcharacter
conjugation between the lone pair of the exocyclic N-atom in
conjunction with the high -deficiency of the s-triazine ring.
There is a restricted rotation thereby induced. Variable tem-
due tothe p/p
13b,d
ported by us in the case of compound 2a (Scheme 1)
failed. This
was the case even under much milder conditions. The dendrimers
rapidly decomposed.
p

8950
F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
Chart 2. Rotational prodiastereomerism of ‘model compound’ 2a as issued from (VT) 1H NMR data.
perature NMR spectroscopy is an appropriate technique for moni-
toring this.20
time, to protons NH and OH (Table 2, Fig. I in SD 2). However, the
1
1
2D- H, H-NOESY charts were unable to disclose any dipolar in-
teraction betweenamino(poly)olic andazaspiranicsitesin anyof the
rotamers of series 4aed a priori designed as anti. Therefore, a DFT
calculation in the case of compound 4a was performed, despite the
fact that the ratio between the two rotational states of 4aed (around
The effect of this phenomenon on iterative amino-s-triazine
11,14,21
synthesis, however, has been much less well-studied.
We
therefore resolved to examine, from rotational point of view, the
status (static or dynamic) of our five series of compounds aee. We
11b,13d,21
revisited the terminology that we had recently proposed.
75:25 anti/syn) was consistent with a DD
less than 1 kcal/mol. The results are summarised in Table 3.
G
298 wꢁ2.72 kJ/mol, i.e.,
This applies where C(s-triazine)eN(exocyclic) partial double bonds
are seen as innate (pro)stereogenic axes, i.e., axes of prodiaster-
eomerism or axes of diastereomerism. On rising the temperature, the
free motion acquired is described as homomeric (topomerisation) or
diastereomeric.
For each rotamer 4a-anti and 4a-syn, three conformers about
sp3
serinolic the NHeC
bond were optimised. Only the B3LYP/6-
311þþG**/CPCM/model provided results in line with our postu-
s
lated ‘dipole rule’. In DMSO, plausible barriers to rotation
DG
(
syn%anti) were found if compared to those resulting from the VT
1
z
3
.1.1. G-0 chlorodendrons. Solvation determining rotameric abun-
H NMR spectral analyses (see Table 2 and later discussion).
At room temperature, the rotational prodiastereomerism was
1
dance. Our analysis started with a brief (VT) H NMR inspection of
the a priori designed ‘model compound’, the N,N -symmetrically
0
13
detectable on the C NMR timescale only as diastereotopicity Dd
between azaspiranic positions
C
0
00
0
00
substituted chlorodiamino-s-triazine 2a (Scheme 1, Chart 2,
a
versus
a
and
b
versus
b
in the
13d
1
SD 1).
At room temperature, the discrimination between azaspiranic
major anti rotamer (Table 2). On H NMR spectra, the signal reso-
lution of protons H- and H- was not amenable for kinetic cal-
culations (Table 2; Fig. I in SD 2; Fig. II in SD 3). Upon heating, no
clear coalescence was observed for H- . For H- , a T w308 K, found
earlier for H- in the ‘model’ compound 2a (Chart 2), was assigned
a
b
0
00
0
00
b
diastereotopic positions as
d (a
H
)>d
H
(a
) and
d
H
(
b
)>
d
H
(
b
) was
against
0
0
made based on the closer proximity of nuclei
a
and
a
b
c
0
0
00
a
and
b
with respect to the dipole moment of bond C-2(s-tri-
a
azine)eCl, i.e., this bond was considered a strong deshielding fac-
in series 4aed. As in the case of 2a, the final dynamic status of
compounds 4bed was a global pseudo freely rotating one. We felt
we had to conclude that the local homomeric rotation
(topomerisation) about the C(4)eN(exocyclic) bonds in un-
8
d,11b,21
tor.
assignment ‘the dipole rule’.
rotating status (fast exchange) at 343 K.
temperature was increased further, at 353 K, a new anisochrony
was exhibited by methylenes H- As this chemical non-
For the present discussion, we will henceforth call this
11b,13d,21
Compound 2a reached freely
2
2aec
To our surprise, when
symmetrical compounds 4aed, was similar to that of symmetric s-
s
a.
triazine 2a, hence
D
G ¼66.11ꢃ0.25 kJ/mol.
equivalence was only 14.5 Hz, the hypothesis that it could origi-
nate from a geminal diastereotopicity induced by the well-docu-
The analysis in serinolic sequence about the C(6)eN(exocyclic)
bonds focused on a process equilibrating two unequally populated
2
3
s
mented axial chirality in spiranes could be ruled out.
therefore called this unexpected dynamic behaviour of compound
a its pseudo freely rotating status. This could be caused by some
We
sites, 4aed-anti>4aed-syn. Accordingly, two
DG
values,
s
s
D
G
ða/sÞ >
D
G
ðs/aÞ, defining two first-order kinetic pro-
anti
anti
22d
2
cesses, were evaluated by applying the method of Shanan-Atidi
(Table 2; Table I in SD 4).
residual steric hindrance between the two azaspiranic fragments
preventing complete fast rotation, combined with the pyramidal
The same type of calculation was then carried out for symmetri-
2
0e,f
0
inversion of their aza-atoms.
cally N,N -substituted chlorodiamino-s-triazine 4e in which, at room
0
Next, we turned our attention to the unsymmetrically N,N -
substituted chlorodiamino-s-triazines 4aed (Tables 2 and 3). Once
temperature, the C(s-triazine)eN(exocyclic) partial double bonds
were two axes of diastereomerism. Consequently, we had to take into
account an equilibrium involving three components (Chart 3).
According to the ‘dipole rule’, a distinction between frozen
rotamers, 4e-(aea), -(aes) and -(ses) was made. In order to
1
3d,21b
again the rotational analysis appears to be original to us.
Only
0
symmetrically N,N -substituted chlorodiamino-s-triazines have
11b,20b,c
been investigated in this way before.
At 293 K, a two-term frozen diastereomerism occurred about the
bond C-6(s-triazine)eN(exocyclic) and was non-statistical. Two
blocked rotamers 4aed-anti (major) and 4aed-syn (minor) were
preliminarily assigned according to the ‘dipole rule’ applied, this
z
More rigorously, if all three conformers in each series 4a-anti and 4a-syn are
considered together with the Boltzmann statistics of their energy level population,
the calculated rotameric ratio was anti/syn 64:36.

F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
8951
Table 2
Two terms rotational (pro)diastereomerism of compounds 4aed as issued from (VT) NMR data
examine, however, their rotational deblocking, we simplified the
problem. We have done so in two respects: (i) by neglecting the
incidence of the minor rotamer 4e-(ses) and (ii) by considering
a single rotation around C(s-triazine)eN(exocyclic) bonds/equilib-
rium. We assume here value of these simplifications on the bases of
(i) A global topomerisation of rotamer 4e-(aes)%4e-(sea),
equilibrating two equally populated sites, took place first, most
probably via the neglected minor 4e-(ses) (T
(ii) Deblocking of the most stable 4e-(aea) species occurred at
a higher temperature (T 336 K), but close to that we already
c
321 K).
c
11b,21b,24
our previous account of them.
encountered for the unsymmetrical analogues 4a, 4b and
4d (338 K, Table 2). The usage of the Shanan-Atidi algorithm
provided kinetic parameters for the equilibrium, 69% 4e-(aea)%
31% 4e-(aes), with 4e-(ses) being approximated as 0%.
Then, by monitoring the 1H NMR NH line shape against the
progressively increasing temperature (Chart 3; Fig. III in SD 5), we
deduced that:

8952
F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
Table 3
s
2
Bond orders (B.O.), dipole moments
blocked rotamers of compound 4a versus their H NMR abundance (%)
m
(D), ZPE corrected relative energies
DH
0K (kJ/mol), relative free energies
DG
298 (kJ/mol) and transition states
D
G
(TS) (kJ/mol) of
98
1
B.O.a
m
D
H
0K
DG
D
G
s
(a/s)
B.O.
m
DH
D
G
298
D
G
s
(s/a)
298
298
2
98
0K
C(4)eNo
C(6)eNo
C(4)eNo
C(6)eNo
B3LYP/6-31G
d
*
*
(gas phase)
d
5.58
7.20
2.34
0.08
0.00
0.00
2.34
1.05
0.00
0.00
74.46
71.49
69.52c
d
d
d
5.31
7.17
7.86
7.50
0.00
0.00
1.13
0.75
0.13
0.00
0.92
0.71
76.72
72.53
68.60c
d
B3LYP/6-31G
d
/CPCM/DMSOb
d
d
d
B3LYP/6-311þþG**/CPCM/DMSO
1.25
1.23
7.30
1.24
d
1.23
d
B3LYP/6-311þþG**/CPCM/THF
d
d
7.03
a
Wiberg bond order calculated within the NBO (natural bonding orbital) analysis applied to the depicted C(s-triazine)eN(exocyclic) bonds.
b
c
The effect of solvent took into account by using the implicit solvent method CPCM (conductor-like polarizable continuum model) implemented in Gaussian 09.
Values to be compared with those provided by VT 1H NMR (Table 2).
Chart 3. Three terms rotational diastereomerism of compound 4e as issued from (VT) 1H NMR data.

F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
8953
All the results reported in this section must, however, be viewed
in the light of the following comments. The s-triazines 4aee, seen
as G-0 chlorodendrons, were not only the most p-deficient, but also
contained the most acidic OH and ‘amide like’ NH groups. We
consider this fact to have possibly important consequences and to
place certain ‘bounds’ on the interpretation of our data.
observed. On heating at 353 K, all G-0 melamines reached fast ex-
change (freely rotating) (Fig. IVa and c in SD 6). No pseudo freely
rotating situation was observed.
On 13C NMR timescales, at room temperature, however, we
observed something different.In serinolic melamines 6aec, the
C(4)eN(azaspirane) bonds were axes of prodiastereomerism be-
0
00
cause azaspiranic carbons C-
a
, -a
were found to be diaster-
22e
(
i) We had to use 1H NMR parameters of exchangeable NH pro-
tons.2 This was because they displayed, in all cases, the best
eotopic. This was the same for related compounds 5a, 5b, 7a and
7b. In compounds 6b and 6c, this rotamerism could be additionally
located about the C(2)eN(piperazine A) bonds, with the piperazine
2a
separated signals. Nevertheless, according to the
d
NH temper-
14,25
0
00
also being diastereotopic. The corresponding
ature gradients (TG)
(Table 2), the NH protons were, at
carbons C-
anisochrony had about the same magnitude as we had encountered
in the more -deficient s-triazines, 4aec-anti (Table 2; Fig. IVb in
b
, -
b
room temperature, not exchangeable at all but located in
a hydrogen bonding environment provided by the solvent,
p
2
0d
DMSO-d
ii) Barriers to rotation (
contents and DdNH T (temperature gradients, TGs, Table 2 and
Chart 3). As recently recommended by Simanek, although
6
(vide infra).
SD 6). For ‘mono-hydroxylated’ melamines 6d and 6e, the above
rotational prodiastereomerism could only be presumed because
s
(
D
G ) correlated well with the rotameric
/D
no Dd
C
diastereotopicity was detected due to broad signals for C-
a
14
(azaspirane) and C-
b
(piperazine A). In all our G-0 melamines, their
2
5
13
this parameter is usually applied to peptides and proteins, it
is generally accepted that if the temperature gradient is more
negative than ꢁ4 ppb/K, in aqueous solution, the NH group is
exposed to solvent and not involved in intramolecular hydro-
gen bonds. In contrast, a temperature gradient less negative
than ꢁ4 ppb/K indicates that the NH protons are, at room
temperature, undergoing intramolecular hydrogen bonding. If
so, although the rotameric contents in series 4aed were
(poly)olic counterpart displayed, clearly, only a single C envi-
ronment as one set of sharp signals for all positions. Hence, the
rotational diastereomerism about the C(6)eN(exocyclic) axes
existed, most likely, as a unique orientation.
In spite of their different construction, all G-0 melamines had TG
values far less negative than their more p-deficient precursors 4aee.
In compounds 6aec, TGs >ꢁ4 ppb/K were indicative of serinolic
NH/OH and NH/N(s-triazine) internal hydrogen bonding. This
reached a maximum in the case of TRIS derivative 6c (TG¼ꢁ1.45
ppb/K). This affinity was not dependent on the melamine structure.
For example, TGs in serinolic series 5e7a and 5e7b were almost the
same, 5a (ꢁ2.55), 6a (ꢁ2.73), 7a (ꢁ2.71) or even identical in 5e7b
(all ꢁ2.36). In contrast, as in series 4aee, for the ‘mono-hydroxylated’
6d and 6e of series 6aee, the intramolecular hydrogen bonding was
the weakest (TG¼ꢁ4.72 and ꢁ3.80, respectively).
comparable, compound 4c, the most ‘hydroxylated’, had the
s
smallest
D
n¼nantiꢁnsyn difference, the smallest
DG
barriers
and the least negative TGs. Compound 4c was the least able to
provide its NH groups to the solvent for hydrogen bonding.
The internal hydrogen bonding ability of the three geminal
hydroxymethyl units of 4c is responsible for this. Conse-
quently, the ground state of compound 4c was the least sta-
bilised by solvent. By contrast, for the most NH/DMSO
Next, in melamines 6a and 6b, each of them having two pe-
ripheral geminal hydroxymethyl units, the OH groups appeared to
be involved in an additional dynamic relationship (Scheme 4), a fast
acidebase intermolecular exchange with piperazine ApNH linker,
solvated G-0 chlorodendron, the ‘mono-hydroxylated’ 4d, we
s
found the highest
D
n, TG and
D
G
values.
(
(
iii) The dominant incidence of rotamers 4aed-(a) and 4e-(aea),
where these have TG <ꢁ4 ppb/K, can also be explained by
stronger NH hydrogen bonding with DMSO, in comparison
with the syn analogues where TG >ꢁ4 ppb/K. The syn com-
pounds appeared to form internal hydrogen bonds. Overall,
2 2
pC(CH OH) %HNoA.
1
1
In the H NMR spectra of 6a and 6b, these H signals were quite
difficult to locate due to a unique and very large singlet mediating
the two different environments (Fig. IVa in SD 6). Moreover, upon
heating, this situation remained unchanged up to 353 K (Fig. IVc in
SD 6). We believe that, in solution, melamines 6a and 6b formed
molecular aggregates.
‘mono-hydroxylated’ compounds 4d and 4e were, regardless
their rotamerism, the most NH solvated, as their TGs disclosed.
s
s
s
iv) The increasing sequence of
DG
values
D
G
<
D
G
<
D
azaspirane
syn
s
G
(Table 2) informed us about the order in which, on heating,
In the geminal ‘tris-hydroxylated’ melamine 6c, we did not detect
an external proton exchange, presumably because of the competitive
anti
these compounds were rotationally ‘activated’ (Fig. II in SD 3).
First, a local homomeric rotation (topomerisation) about the C(s-
triazine)eN(azaspirane)bondoccurs,then,intandemwithalocal
diastereomeric rotation about the C(4)(s-triazine)eN(exocyclic)
bond, to create, finally, a global diastereomeric rotational motion.
To conclude, this order was parallel with an increase in the sol-
vation of the N-ligands solvation: azaspirane<amino(poly)ol as
syn N-ligand<amino(poly)ol as anti N-ligand.
1
internal association of the alcoholic units. The H NMR spectrum
2 3
displayed different peaks for protons eC(CH OH) and ApNH. The
same was valid for ‘mono-hydroxylated’ melamines 6d and 6e.
Furthermore, in piperazine linker A for each of 6aee, one must
0
observe the downfield
d
C
value of carbons C-
a
with respect to C-
b
,
0
0
-b
. We consider this deshielding to also support the above proton
exchange, implying the most basic site, ApNH, of these melamines.
This deprotonates either the two geminal hydroxyl groups as in 6a
6
and 6b or, simply, the traces of water in DMSO-d in the case of 6cee.
By combining all these outcomes, we concluded that:
3.1.2. Analysis of G-0 melamines. rotamerism. Specific NH/OH in-
teractions. Aggregations. When the C-2 chlorine of G-0 dendrons
aee was replaced by a bulky, basic and strong electron donating
piperazine A motif to provide melamines 5e7, three features were
expected (i) a diminished s-triazine ring -deficiency, (ii) a de-
(
i) Owing to the versatile internal versus external NH/OH re-
4
lationships of serinolic units of 6aec, it was their azaspiranic
0
00
counterpart, still exhibiting C-
a
versus Ce
a
diaster-
p
eotopicity, to undergo restricted rotation about the bond
creased bond order C(s-triazine)eN(exocyclic) and (iii) an aug-
mented basicity of s-triazine nitrogens. The data are presented in
Table 4 (see Table II in SD 7 for compounds 5a, 5b, 7a, 7b and 7e).
At room temperature, on 1H NMR timescales, the signals as
broad lines indicative of slow rotational exchange between equally
C(s-triazine)eN(azaspirane).
(
ii) Since the two C(s-triazine)eN(serinol or azaspirane) bond
orders were, normally, very comparable, we conclude the
incidence of electronic factors was unimportant. Therefore,
we assigned the rotational prodiastereomerism of azaspir-
ane fragment to vicinal steric hindrance by the adoption of
(5a, 5b) or unequally (6aee, 7a, 7b, 7e) populated sites were

8954
F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
Table 4
Rotational (pro)diastereomerism of compounds 6aee as issued from (VT) NMR data
the serinolic group of a prevailing anti orientation, as in the
series of precursors 4aec-(a). Once more, we deduced that
this spatial arrangement best exposed the NH and OH
groups to the observed intra- versus extramolecular
interactions.
3.1.3. G-1 and G-2 dendritic compounds. From peripheral, via in-
1
26
ternal, to frontier rotamerism. First of all, 2D DOSY H NMR of our
G-2 dendritic melamines 10 and 11 confirmed their macromolec-
ular nature (Fig. VIaee in SD 8 and Fig. VIIaef in SD 9). Table 5
reports the diffusion coefficients (D) together with the corre-
sponding hydrodynamic diameters, d
H
.
Hydrodynamic diameters d were calculated from the hydro-
H
dynamic radii r
H
by applying the well-known StokeseEinstein
equation (Eq. 1).
kT
rH
D ¼ 6ph ꢂ 10ꢁ
9
(1)
ꢁ
23
where k is the Boltzmann’s constant (1.38ꢂ10
J/K), h is the dy-
ꢁ
3
ꢁ1 ꢁ1
namic viscosity (2.00ꢂ10 kg m
s ) of DMSO at T (298 K) and r
H
(
nm) is the hydrodynamic radius.
We then analysed the dynamic rotational behaviour of the
dendrimers based on two concepts:
(i) Dynamic behaviour around C(s-triazine T-0)eN[azaspirane,
amino(poly)ol] bonds (henceforth called ‘peripheral rotamerism’)
(ii) Dynamic behaviour around C(s-triazine T-0, -1, -2)eN(piperazine
Scheme 4.
A or B, piperidine) bonds (henceforth called ‘internal rotamerism’)

F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
8955
1
Table 5
On the whole, all these H NMR data did not furnish significant
differences concerning the peripheral rotamerism in 8e11 versus
their ‘monomeric’ precursors 6.
Diffusion coefficients (D) and hydrodynamic diameters (d
H
) of compounds 10 and 11
(nm)
Da
(m
m /s)
2
d
H
No.
14
Next, by means of a ‘model compound’, the symmetrically
N,N -disubstituted 2-chlorodiamino-s-triazine 1a, we attempted to
simulate’ the internal rotamerism in chlorodendrons G-1, -2 8aee
and 10aee. The (VT) NMR analysis of compound 1a is summarised
in Chart 5.
Due to the presence of a great number of anisochronous
-methylenic CH eN groups in 8aee and 10aee, we extrapolated
cautiously the results in the case of 1a.
that of double azaspiranic s-triazine 2a (
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
80.9
73.1
101.4
79.2
75.8
65.6
61.0
53.8
72.6
61.1
2.70
2.99
2.16
2.76
2.89
3.34
3.59
4.07b
3.01
3.58
0
‘
11b
a
2
s
D
G of 1a was very similar to
s
D
G ¼66.11ꢃ0.25 kJ/mol,
a
At 298 K as 5 mM in DMSO-d
Identified as a unique macromolecular species in a mixture (Fig. VIId in SD 9).
6
.
s
Chart 2). That is, DG of 1a provided a rough sketch for the operation
b
of rotational behaviour around C(s-triazine, T-1, -2)eN(piperazine A
or B) bonds in 8aee and 10aee. Therefore, we assumed that the local
rotational ‘activation’ about C(s-triazine)eN(azaspirane, piperazine,
piperidine) bonds required not more than w67 kJ/mol, i.e., in the
situation when the most
bis(piperazine-1-yl)-s-triazine, was incorporated by our G-1, -2
We exploited our knowledge of G-0 melamines 6aee, which
p-deficient motif, 2-chloro-4,6-
were seen as ‘references structures’ with respect to their sub-
sequent dimeric 8, 9, tetrameric 10 and octameric 11 angularly
coupled homologues.
dendritic compounds.
1
13
By contrast, C NMR data were much more informative. Thus,
At room temperature, all compounds 8e11 exhibited broad H
13
NMR resonances that were consistent with slow rotational pro-
cesses. By increasing the temperature at 353e363 K, they displayed
convincing line shapes, in accord with an acquired mobility (Fig. Va
and b in SD 10).
Furthermore, inspection of temperature gradients showed
values, which were not too sensitive to the increase of molecular
dimension (Chart 4; Table III in SD 11).
at room temperature, on C NMR timescales and for all relevant
aspects of series 8e11aed, the C(s-triazine T-0)eN(azaspirane)
bonds still remained peripheral axes of prodiastereomerism. This,
at any rate, was our finding on the basis of azaspiranic carbons
0
00
C-a
, -a
, which were found to be diastereotopic (Chart 6; Fig. VIII
values had similar size to those established for
G-0 precursors 6aed (Table 4).
in SD 12). Their Dd
C
We already mentioned that G-1 melamines 9a and 9b did not
aggregate in solution. Nevertheless, as in G-0 melamines 6aee
In the ‘Methylserinolic’ series 6e11a, all compounds had iden-
tical TGs (ꢁ2.73 ppb/K); it is our contention that this was so be-
cause they kept the same kind of intramolecular NH/OH
association. One discrepancy was observed in the related ‘Ethyl-
serinolic’ series 6e11b with TG values of ꢁ2.36 ppb/K in 6b, 9b and
(Table 4, Scheme 4), in the piperazine B rings of series 9aee, we
observed a downfield shift of their -carbons. Therefore, our as-
a
signment was the same as that in the case of 6a-e, namely a fast
proton interchange, this time as BpNH%HOH (Chart 6).
1
0b but a TG of ꢁ1.45 ppb/K for chlorodendron 8b. However,
Furthermore, compounds 10a-e, 11a, 11b and 11e were in-
dendrimers 11a and 11b had an identical TG, ꢁ2.73 ppb/K. As ex-
pected, TRIS based derivatives 8e10c had the least negative TGs. As
in series 8e11b, the NH groups had the most internal association in
13
vestigated by QC C NMR spectroscopy (Fig. IX in SD 13; Fig. Xaed
13
in SD 14). Now, we found on the one hand that QC C calculation of
0aee was routine; no difference between G-2 chlorodendrons of
series 10aee was noticed. On the other hand, in G-2 dendritic di-
1
chlorodendron 8c (TG¼ꢁ0.91 ppb/K) followed by
1.38 ppb/K in compounds 9c and 10c (ꢁ1.45 ppb/K in the ‘refer-
ence’ 6c). Like G-0 melamines 6d and 6e, in series 8e11d and
e11e, the lone hydroxyl group/aminoalcohol peripheral unit was
a TG of
ꢁ
1
3
1
mers 11, combined QC C NMR and (VT) H NMR data revealed
0
perturbation of the magnetic environment of the 4,4 -bipiperidine
8
central linker (Chart 7).
least available to bind to the neighbouring NH proton. In these
series we found the most negative TGs. Illustratively, dendrimer
13
This perturbation consisted of deshielding of the C positions 2,
, 6, 6 and shielding of the H positions 3, 3 , 4, 4 , 5, 5 in 11e with
0
0
1
0
0
0
2
1
1d had the most NH/DMSO solvation (TG¼ꢁ5.27 ppb/K).
respect to 11a, 11b and 11d. Since the constitution of the dendritic
networks in series 11 was identical except the peripheral units, our
assumption was that it was the peripheral units to which we should
look to account for this difference.
Differently than their building-blocks G-0 6a and 6b (Table 4,
Scheme 4), G-1 melamines 9a and 9b formed no external aggre-
2 2 H
gates of type pC(CH OH) %HNoB since individual d values were
found for the depicted ‘mobile’ protons (Fig. Vb in SD 10).
The answer we reached was provided, unexpectedly, by the QC
13
13
C calculation (Schemes 5 and 6, Fig.1). Firstly, the integration of
C
0
signalsin11e wasinagreement, in boths-triazinesringsT-2, -2 , with
the same normal anisochrony, two types of C-nuclei as six carbons in
0
0
0
a 4:2 ratio,
d [(C-4)h(C-4 )h(C-6)h(C-6 )]sd [(C-2)h(C-2 )].
C
C
Therefore, in 11e, it was credible that, regardless any rotational ori-
entation (ses), (aes) or (aea) of its peripheral N-ligands, internal
0
0
0
0
1b( )
2
a( )
2b( )
1a( )
topomerisations of branches R
%R
, R
%R
(Scheme 5)
with respect to the axes of prodiastereomerism C(s-triazine)eN(pi-
perazine, piperidine) occurred randomly.
To our surprise, in compounds 11a and 11b, calculation discov-
ered three types of C-nuclei for the six s-triazine carbons in a 2:2:2
ratios, i.e., the same three different ‘unpaired’ carbons for each
‘
monomeric half’ of the dendrimer. We normally located them in
0
the ‘unpaired’ T-2, -2 s-triazine rings (Scheme 5).
13
On the C NMR timescale, just two statistically planar for-
mulations corroborate this assignment (Scheme 6). Firstly, iso-
0
0
( )
0
0
0
Chart 4. Temperature gradients (TGs) of compounds 6, 8e11.
chronous s-triazines T-2 C-nuclei 446 and 4 46 or 444

8956
F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
α
α
Δ
Δ
Δ
α
α
Chart 5. Rotational prodiastereomerism of ‘model compound’ 1a as issued from (VT) 1H NMR data.
0
and 646 were also homotopic because rotamers 11a-, 11b-
dendritic rotamers 11a-, 11b-[(aes)j(sea)] against 11a-, 11b-
[(sea)j(sea)] were non-chiral (meso-form) and chiral, respectively.
If so, the relationships between the 2ꢂ(1:1:1) ‘unpaired’ carbons
x
[
(aes)j(sea)] were C2S whereas 11a-, 11b-[(s-a)j(s-a)] were C
i
symmetric. Secondly, only in 11a and 11b were there lateral
0
branches R1 and R (Scheme 5) that had to accommodate two
different bulky peripheral units. Consequently, the depicted
steric orientation, designed simply as ‘serinol against serinol’,
we saw the preferred one. Furthermore, this allowed multiple
hydrogen bindings. These binding we might term an ‘inner
dendritic communication’, which thus created a pseudo-macro-
a
1a
become: C-4 against C-6 and C-4 against C-6 are enantiotopic in
0
0
meso-11a-, 11b-[(aes)j(sea)] meanwhile, in chiral 11a-, 11b-
0
0
[(sea)j(sea)], C-4 against C-4 and C-6 against C-6 remain
homotopic.
0
0
1
a
1b
1a
1b
3.2. Analysis in solid state by AFM imaging
cyclic cavity. Hence, we have R sR and R sR . That is, in
spite of an exacerbated C(s-triazine)eN(exocyclic) rotational
diastereomerism of 11a and 11b, only two of its locations were
relevant: the internal one, around bonds C[s-triazine T-0 ]eN
piperazine A ], in tandem with the peripheral one, in respect of
Given the above, it made sense to subject compounds 11b, 11d
and 11e to structural analysis in the solid state. We did this by the
technique of AFM (atomic force microscopy), a method the rarely
0
(
)
0
(
)
[
0
5c
(
)
mentioned in the field of dendritic melamines. AFM can provide
C[s-triazine T-0 ]eN(serinol A or B) (Scheme 5). They generated
the two depicted dendritic rotamers for which inclusion apti-
tudes as an ‘open gates’%‘closed gates (ineout)’ process should
be anticipated. We have termed this novel behaviour ‘frontier
rotamerism’. Since the two ‘monomeric halves’ are homomor-
phic, the simplest way by which the two dendritic rotamers can
interchange, [(aes)j(sea)]%[(sea)j(sea)], is the rotation of
new evidence about the shape and the size of dendritic particles or
aggregates self-assembled in adsorbed coating films on solid sur-
3
,27
faces.
There are obvious applications in nano-science. However,
it must be noted that morphologies (aggregates) observed by AFM
may be rather different to those present in solution as a conse-
quence of drying and surface effects.
Dendrimers 11b, 11d and 11e were self-assembled on mica, as
solid support, by their adsorption from a 1 mM organic solution.
Under controlled conditions, they provided coating films at satu-
ration of the solid surface. These adsorbed films were characterised
by AFM operating in tapping mode (TM).
The results of our imaging process are shown in Figs. 2e4. They
show that our compounds strongly adsorbed on mica in large ag-
gregates (islands and clusters). These aggregates were of globular
shape and relatively uniform size, the adsorbed films being roughly
monodisperse.
Fig. 2 shows AFM images of dendrimer 11e; we see many well-
defined globular particles randomly adsorbed on mica. These par-
ticles appear to be substantially uniform in size, with an average
lateral dimension of about 60ꢃ5 nm, indicating that the adsorbed
film was rather monodisperse. Nevertheless, there do appear to be
a few larger aggregates, of dimensions up to 100 nm. Such images
show, furthermore, that dendrimer particles of 11e were apparently
made from supramolecular nano clusters, self-assembled within
the coating layer of slightly low surface roughness, given by rms
0
0
(
)
( )
a single ‘monomeric half’ about the C-2 [s-triazine T-2 ]eN-
0
(
)
0
1
(4,4 -bipiperidine) bond.
We further observe that a third C2S formulation for 11a, 11b as
[
(aea)j(ses)] (‘open gates’) (Scheme 6) should, in fact, be ruled out
0
0
because it involves
d
C
[(C-4)h(C-6)]s
d
C
[(C-4 )h(C-6 )], hence
d
C
0
0
( )
(
C-2)sd
C
(C-2 ), i.e., four types of s-triazines T-2 C-nuclei as six
carbons in a 2:1:1:2 ratio.
Unfortunately, due to its very low solubility in DMSO, dendrimer
1d did not allow us to obtain a convincing QC C NMR spectrum.
Therefore, based on its H (Fig. IXc in SD 13) and DEPT C NMR data
Chart 7), we could only presume that it also belongs to the same
family as 11a and 11b.
13
1
1
13
(
Some account might be given that involved the well-known
phenomenon of dendritic backfolding,3,14 though any such ac-
count would have to be carefully adopted. If so, one would want
note that, as shown in Table 5, the hydrodynamic diameters d
nm) of our dendrimers were almost identical for 11b (3.59)
versus 11e (3.58). Therefore, if (and this is just an hypothesis) 11a
and 11b were back-folded, in solution, the non-planar resulting
H
(
(defined by the root mean square of the height distribution) value
on scanned area, of about 9ꢃ2 nm.
The AFM experiments, performed with compound 11b (Fig. 3),
also support the hypothesis of the formation of a globular mor-
phology on mica at the adsorption time of 1 h. This phenomenon
x
Symbol ‘j’ designs the peripheral ‘frontier’ between the two ‘monomeric halves’
of the dendrimer.

F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
8957
Chart 6. Peripheral rotamerism of compounds 8e11 as issued from (QC) 13C NMR data.
leads, in turn, to the surface saturation with an average lateral size
of about 46ꢃ4 nm for dendrimer particles. The resulting coating
film of dendrimer 11b shows a rather low roughness of about
Comparatively, one can clearly observe that globules of den-
drimer 11e (Fig. 2) were wider (lateral size of particles between 56
and 85 nm) than those of both 11b (width from 30 to 65 nm,
Fig. 3) and 11d (width from 24 to 43 nm, Fig. 4) for each coating
film obtained after an adsorption time of 1 h on mica. This is not
surprising as the aggregates of dendritic molecules are expected
to be larger for dendrimer 11e than for the corresponding aggre-
gates of dendrimers 11b and 11d adsorbed onto the mica surface,
in substantial agreement with their molecular structure and with
11ꢃ3 nm.
These morphological features were similar to those observed in
the case of compound 11d (Fig. 4). Specifically, the AFM images
clearly showed adsorbed aggregates of compound 11d with an
average lateral size of about 37ꢃ4 nm and a very low roughness of
about 6ꢃ2 nm.
0
Chart 7. Comparative details from NMR spectra (5 mM in DMSO-d
6
) of compounds 11a, 11b and 11d with respect to 11e in the 4,4 -bipiperidine central linker zone.

8958
F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
Scheme 5.
the different kind of interaction with the surrounding medium.
The surface roughness, rms, on scanned area of 1 m, in-
mꢂ1
to the G-2 chlorodendron stage. The same strategy was also
valid for 2-amino-2-methylpropanol as a unique peripheral
unit.
m
m
dicated that dendritic films were almost flat, with compound 11e
having an rms value of 9ꢃ2 nm, 11b an rms of 11ꢃ3 nm and 11d an
rms of 6ꢃ2 nm. We can speculate, with some plausibility, on the
origin of such flattened dendritic aggregates. It might be attrib-
uted to their ready adsorption on hydrophilic mica as a conse-
quence of the hydroxyl termini functionalities on all investigated
compounds.
(ii) The structural analysis of our amino-s-triazines was based on
combined NMR methods. This was so because of the main
focus on the restricted rotations phenomena around the C(s-
triazine)eN(exocyclic) partial double bonds. For G-0 chlor-
odendrons, canonical algorithms (Eyring, Gutowski-Holm and
Shanan-Atidi) provided pertinent kinetic results. The dynamic
behaviour of our compounds (rotamerism, acidebase in-
terchange and aggregation) was dictated, mainly, by solvation
effects involving the amino(poly)olic units. Their G-0/G-2
complexity did not seem to affect this.
The resulting adsorbed species self-assembled in rather compact
networks and this can be observed across all the AFM images. They
exposed a compact packing of individual dendrimer aggregates in-
side theircoating film. Our macromolecules strongly interacted with
the mica surface primarily through hydrophilic interactions of their
peripheral OH groups in a natural tandem with the hydrophilic na-
ture of mica.
(iii) The ethylene ketal of 4-piperidone counterpart was the most
relevant marker for the existence of rotamerism because the
bond C(s-triazine)eN(azaspirane) was, continuously, an axis of
prodiastereomerism.
To conclude, we assume that the morphology of adsorbed lay-
ered networks was assisted by the nature of the self-assembled
2
7c
structure of our dendrimers.
Considering rms values, com-
This includes G-1, -2 dendritic compounds (‘peripheral rotamerism’).
pound 11d was adsorbed on mica in a rather flattened nano-
structured film when compared to compounds 11e and 11b. The
slight differentiation probably originates from the different in-
teraction among particles and with the organic solvents present
during the adsorption of dendrimers on mica surface, as well as
with the mica surface.
(iv) Starting from G-1 dendrons, their ‘internal rotamerism’ could be
s
approximated by structural simulation. Overall, the
DG
rota-
tional barriers in all our melamines did not exceed 67 kJ/mol.
(v) If the peripheral units of G-2 dimeric melamines were the
tandem (Methyl- or Ethylserinol)-(ethylene ketal of 4-
piperidone), a new type of ‘frontier rotamerism’ dynamic ‘open
gates%closed gates’ behaviour was observed, and this affected
the adjacent branches subsequent to dendritic dimerisation.
4
. Conclusions
(
i) We report the seven-step convergent synthesis of a new family
of dimeric G-2 dendritic melamines with a commercial
amino(poly)ol (C-2-substituted serinols or 2-amino-2-
methylpropanol)dethylene ketal of 4-piperidone tandem as
peripheral units. This was effected by iterative chemoselective
aminations of cyanuric chloride. This synthesis occurred with
a range of yields from satisfactory to good, except the case of
TRIS, for which the proposed chemistry was applicable only up
(vi) Comparative AFM investigations showed that our G-2 den-
dritic melamines were self-assembled globular structures,
which exist as monodispersed films on mica. Nevertheless,
globules of the dendritic melamine with peripheral 2-methyl-
2-propanol units were thicker and wider than those obtained
from the corresponding analogues possessing the termini
tandem serinol-ethylene ketal of 4-piperidone.

F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
8959
Scheme 6.
Fig. 1. Comparative details from QC 13C NMR spectra (125 MHz timescale, 5 mM in DMSO-d
, 298 K) of compounds 11e, 11a and 11b in the s-triazines zone.
0
6

8960
F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
Fig. 2. AFM images for compound 11e adsorbed for one hour on mica from 1 mM DMSO solution; (a): 2D topography; (b): phase image; (c): amplitude image; (d): 3D topography;
e): profile of the cross section along the arrow in panel (a). Scanned area of 1 m. Surface roughness given by root mean square (rms) on scanned area is about 9 nm (ꢃ2 nm).
mꢂ1
The standard deviation is denoted in parentheses.
(
m
m
5
5
. Experimental section
.1. General
spectra were measured in anhydrous commercially DMSO-d
one sample/75 ml bottle. All chemical shifts ( values) are given
throughout in parts per million (ppm); all homocoupling patterns
6
as
m
d
n
(
J
H,H values) are given throughout in hertz. TLC was performed by
Ò
Melting points are uncorrected; they were carried out on
using aluminium sheets with silica gel 60 F254 (Merck ); column
ELECTROTHERMALÒ instrument. Conventional NMR spectra were
recorded on a Bruker AM 300 instrument operating at 300 and
chromatography was conducted on Silica gel Si 60 (40e63 mm,
Ò
Ò
Ò
Merck ). IR spectra were performed on a PerkineElmer Paragon
1
13
7
5 MHz for H and C nuclei, respectively. (VT) NMR spectra and
FT-IR Spectrometer. Only relevant absorption maxima are listed,
Ò
ꢁ1
related experiments were recorded either on a Bruker AM 400
instrument operating at 400 and 100 MHz for H and C nuclei or
on a Bruker AM 500 instrument operating at 500 and 125 MHz
for H and C nuclei, respectively. In these last instruments, NMR
throughout, in cm . Microanalyses were performed on a Carlo
1
13
Ò
Erba CHNOS 1160 apparatus. Mass spectra (MS) were recorded as
Ò
Ò
follows: FAB Spectra on a JEOL AX500 Instrument equipped with
1
13
Ò
a DEC DA 5000 computer and ionisation realised with a FAB JEOL
Fig. 3. AFM images of compound 11b adsorbed for 1 h on mica from 1 mM DMSO solution; (a): 2D topography; (b): 3D topography; (c): profile of the cross section along the arrow
in panel (a). Scanned area of 1 m. rms on scanned area is about 11 nm (ꢃ3 nm).
mꢂ1
m
m

F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
8961
Fig. 4. AFM images of compound 11d adsorbed for 1 h on mica from 1 mM mixed solution of CHCl
3
/abs EtOH (3:1, v/v); (a): 2D topography; (b): 3D topography; (c): profile of the
cross section along the arrow in panel (a). Scanned area of 1 m. rms on scanned area is around 6 nm (ꢃ2 nm).
mmꢂ1
m
ꢀ
ꢀ
Cannon (fascicle of Xenon accelerated under 4 kV/10 mA); MALDI
spectra on Micromass TOF-SpecE MALDI Instrument equipped
reaction mixture was kept at ꢁ10 C (ꢁ15 C) for an additional 36 h
then allowed to reach room temperature very slowly. After filtering
minerals, water (50 mL) and chloroform (100 mL) were added to
the organic solution. The aqueous layer was extracted with chlo-
roform (2ꢂ35 mL) and the combined organic layer was washed
with water (3ꢂ35 mL) to neutrality. After drying over anhyd
Ò
with a time of flight analyser and a nitrogen pulsed laser
Ò
(
337 nm); ESI spectra on a Bruker Esquire Instrument with ions
trapping in electrospray mode. Except DMF, all reagents and
solvents were of commercial quality and used as such with no
supplementary purification. Only DMF was freshly distilled prior
to use.
2 4
Na SO , the organic solution was evaporated under reduced pres-
sure to dryness to provide 2.88 g crude product, which was crys-
tallised from boiling ethanol (6 mL) to yield, after standing for 24 h
at ꢁ18 C, the pure title compound 4d (2.42 g, 85% yield with re-
The synthesis and data of compounds 1a and 2a (Scheme 1)
11b,13bed
ꢀ
we reported, in detail, elsewhere.
Complete character-
isation of the non-isolated intermediates 3aec we reported
elsewhere.1 For the present study, isolation of 3d was not
considered of interest because of the good and reproducible
result obtained in the preparation of 4e (Table 1, entry 4). The
synthesis and data of compounds 4aec, 5a, 5b, 7a, 7b (Scheme
spect to cyanuric chloride).
1b
5.1.1.1. 2-Chloro-6-{[1-hydroxy-2-(methyl)prop-2-yl]amino}-4-
(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazine (4d). White crys-
talline solid, mp 143.8e144.5 C (EtOH). Found: C, 49.11; H, 6.77; N,
ꢀ
13d
2
) we reported elswhere.
For the present discussion see
20.22%. C14H22ClN
5
O
3
(343.14) requires C, 48.91; H, 6.45; N,
max (KBr) 3430, 3301, 2990,
Tables 1, 2, and 4, Table II in SD 7, Fig. I (compound 4b) in SD 2,
Fig. II (compound 4b in SD 3) and Fig. IVaec (compound 6a) in
SD 6.
20.37%; R (75% Ligroin/acetone) 0.52; n
f
2960, 2931, 2878, 1573, 1537, 1504, 1453, 1406, 1362, 1308, 1232,
1149, 1120, 1188, 1088, 1056, 1028, 948, 889, 800, 704, 658,
ꢁ
1
In the NMR descriptions, some specific abbreviations were used:
622 cm
(4H, t, J 5.8 Hz, H-6, -10, a.s.), 3.49 (2H, s, CH
5.8 Hz, H-7, -9, a.s.), 3.93 (4H, s, H-2, -3, a.s.), 4.56 (1H, br s, OH),
6.75 (1H, br s, NH) ppm; (100 MHz, DEPT, DMSO-d , 293 K) 23.9
;
d
H
(400 MHz, DMSO-d
6
, 353 K) 1.31 (6H, s, Me), 1.66
‘
br t’ (broad triplet), ‘br d’ (broad doublet), ‘br m’ (broad multiplet),
ot’ (overlapped triplet), ‘A’ or ‘B’ (piperazine linkers), T-0, -1, -2
2
OH), 3.78, 77 (4H, ot, J
‘
(
s-triazine, branch cells), AeD [amino(poly)ol, peripheral units], a.s.
d
C
6
0
(
azaspirane) and bip (4,4 -bipiperidine, central linker) (Schemes 2
(Me, anti), 24.3 (Me, syn), 34.6, 34.8 (C-6, -10, a.s., anti, syn), 41.4,
41.8, 42.0 (C-7, -9, a.s., anti, syn), 55.1 (C-2, D, anti), 55.3 (C-2, D,
and 3).
syn), 64.3 (C-2, -3, a.s., syn), 64.4 (C-2, -3, a.s., anti), 67.1 (CH
2
OH,
5
.1.1. Typical procedure for the synthesis of compounds 4aed. Prep-
aration of compound 4d (Scheme 3). To anhyd K CO (1.15 g,
.30 mmol) suspended in a dry THF (75 mL) solution containing
anti), 67.7 (CH OH, syn), 106.9 (C-5, a.s., anti), 107.0 (C-5, a.s., syn),
2
2
3
163.6 (C-4, T-0, syn), 164.0 (C-4, T-0, anti), 165.0 (C-6, T-0, anti),
165.7 (C-6, T-0, syn), 168.5 (C-2, T-0, anti), 168.6 (C-2, T-0, syn)
ppm; m/z (CI positive, 200 eV, t-BuH) 400 (Mþi-BuHꢁ1) (9), 344
8
cyanuric chloride (1.53 g, 8.30 mmol), solid 2-amino-2-
methylpropanol (0.740 g, 8.30 mmol) was added, at room temper-
ature, with vigorous stirring. The stirred suspension was kept at
room temperature for an additional 24 h. when TLC monitoring
þ
(MH ) (100), 310 (10%).
5.1.2. Preparation of compound 4e (Scheme 2). To anhyd K
2
CO
3
ꢀ
(
toluene/i-PrOH 2:1) indicated formation of the intermediate 3d as
(2.76 g, 20.00 mmol) suspended in a cooled (ꢁ10 C) dry THF
(75 ml) solution containing cyanuric chloride (1.80 g, 9.76 mmol),
2-amino-2-methylpropanol (1.78 g, 20.00 mmol) as dry THF
(25 ml) solution was slowly injected with vigorous stirring. The
reaction mixture was allowed to reach room temperature and
kept as such for an additional 12 h when TLC monitoring
a single major spot. Water (7.50 mL) and anhyd K CO (2.30 g,
2
3
16.60 mmol) were added and the reaction mixture was cooled at
ꢀ
ꢀ
ꢁ
10 C (ꢁ15 C). At this temperature, solid 1,4-dioxa-8-azaspiro
[
4.5]decane hydrochloride 2 (1.49 g, 8.30 mmol) was added por-
tionwise (five equal portions as 0.298 g/portion each 90 min). The

8962
F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
(
toluene/i-PrOH 2:1) indicated the formation of 4e contaminated
THF was replaced by 1,4-dioxane and refluxing was continued for
an additional 12 h. After this period, TLC monitoring revealed the
presence of 4e and 6e in small traces only. Solids were filtered off
and thoroughly washed with dry THF. The organic filtrate was
evaporated under reduced pressure to dryness. Column chroma-
with the corresponding intermediate the N-substituted-2,4-
dichloro-s-triazine. The reaction mixture was heated to 45 C
ꢀ
for an additional 13 h when TLC monitoring revealed completion
of the amination, then cooled at room temperature. Solids were
filtered off and well washed with dry THF. The organic filtrate
was evaporated under reduced pressure to dryness and the
resulting white powder was crystallised from min. boiling etha-
nol to afford pure 4e (2.11 g 75% yield with respect to cyanuric
chloride).
3
tography (CHCl /EtOH 1:1) afforded pure 7e (0.89 g, 76% yield with
respect to piperazine).
5.1.5.1. 1,4-Bis{4,6-bis{[1-hydroxy-2-(methyl)prop-2-yl]amino}-s-
ꢀ
triazin-2-yl}piperazine (7e). White crystalline solid, mp 230e235 C
(
column chromatography, CHCl
N, 28.44%. C26 (592.39) requires C, 52.68; H, 8.16; N,
28.36%; R (50% CHCl /EtOH) 0.80; max (KBr) 3502, 3419, 3346, 3168,
2964, 2931, 1563, 1494, 1440, 1360, 1281, 1254, 1199, 1167, 1060,
3
/EtOH 1:1). Found: C, 52.82; H, 7.89;
5
.1.3. 2-Chloro-4,6-bis{[1-hydroxy-2-(methyl)prop-2-yl]amino}-s-
48 12 4
H N O
ꢀ
triazine (4e). White crystalline solid, mp 171.4e172.3 C (EtOH).
f
3
n
Found: C, 45.77; H, 6.69; N, 23.98%. C11
quires C, 45.60; H, 6.96; N, 24.17%; R (66% toluene/i-PrOH) 0.80;
max 3370, 3271, 2980, 2839, 1598, 1532, 1474, 1301, 1270, 1196,
5 2
H20ClN O (289.13) re-
ꢁ
1
f
1048, 1017, 994, 898, 833, 809, 743, 595, 563 cm
DMSO-d , 353 K) 1.32 (24H, s, Me), 3.45 (8H, s, A), 3.67 (8H, s,
CH OH), 4.78 (4H, br s, OH), 5.54 (4H, s, NH) ppm; (75 MHz, JMod
DMSO-d , 298 K) 20.8, 20.9 (Me), 42.0 (CH , A), 53.7 (C-2, D),
68.4 (CH
H
; d (500 MHz,
n
6
ꢁ
1
1
056, 1037, 996, 903, 803, 770, 704, 667, 531, 510 cm
500 MHz, DMSO-d , 353 K) 1.32 (12H, s, Me), 3.48 (4H, d, J
.0 Hz, CH OH), 4.61 (2H, br s, OH), 6.52 (2H, br s, NH) ppm;
125 MHz, DEPT, DMSO-d , 298 K) 24.0, 24.1 (Me), 54.9 (C-2, D,
anti), 55.0, 55.2 (C-2, D, anti, syn), 67.4, 67.9 (CH OH, anti, syn),
7.7 (CH OH, anti), 164.6, 165.4 (C-4, -6, T-0, anti, syn), 165.0
C-4, -6, T-0, anti), 167.38 (C-2, T-0, anti), 167.43 (C-2, T-0, anti,
;
d
H
2
d
C
,
(
6
(
6
6
2
2
d
C
2
OH), 164.0 (C-2, T-0), 165.0 (C-4, -6, T-0) ppm; m/z (DCI
þ
6
positive, 200 eV, i-BuH) 649 (Mþi-BuHꢁ1) (5), 593 (MH ) (100), 562
2
(10%).
6
(
2
5.1.6. Typical procedure for the synthesis of compounds 8aee. Prep-
syn) ppm; m/z (DCI positive, 200 eV, i-BuH) 346 (Mþi-BuHꢁ1)
aration of compound 8e (Scheme 3). To anhyd K
2
CO
3
(0.44 g,
þ
þ
ꢀ
(
(
15), 312 (MNa ) (10), 290 (MH ) (100), 346 (15), 312 (10), 256
50), 224 (10), 73 (10%).
3.18 mmol) suspended in a cooled (ꢁ10 C) dry THF (50 ml) solu-
tion containing cyanuric chloride (0.29 g, 1.57 mmol) and with
vigorous stirring, compound 6e (1.17 g, 3.45 mmol) as dry THF
(25 mL) solution was injected very slowly. The reaction mixture
was allowed to warm up to room temperature overnight when TLC
monitoring (toluene/i-PrOH 2:1) revealed the presence of 8e as
well as the unreacted 6e. THF was replaced by 1,4-dioxane and the
5
.1.4. Typical procedure for the synthesis of compounds 6aee. Prep-
aration of compound 6e (Scheme 2). To anhyd K CO (0.96 g,
.90 mmol) suspended in a dry THF (50 ml) solution containing
anhyd piperazine (2.37 g, 27.51 mmol), compound 4e (2.00 g,
.90 mmol) as dry THF (20 mL) solution was added portionwise,
with vigorous stirring, at room temperature. After addition of each
ml of this 4e THF solution, over 90 min, TLC monitoring estab-
lished complete consumption of 4e (toluene/i-PrOH 2:1) and for-
mation of the desired 6e (CHCl /EtOH 1:1) as major product versus
2
3
6
ꢀ
6
reaction mixture was heated at 90 C for an additional 11 h when
TLC monitoring confirmed the formation of 8e as major product. At
ꢀ
4
90 C, solids were filtered off and thoroughly washed with dry and
hot THF. The organic filtrate was evaporated under reduced pres-
3
sure to dryness and the resulting crude product was triturated
ꢀ
the corresponding 1,4-disubstituted piperazine derivative 7e.
Solids were filtered off and thoroughly washed with dry THF. The
organic filtrate was evaporated under reduced pressure to dryness
and the solid residue was separated by column chromatography on
silica gel to yield, firstly, the side-product 7e (0.10 g, 5% partial
at ꢁ18 C with EtOH/Et
2
O affording pure 8e (1.12 g, 90% yield with
respect to cyanuric chloride).
5.1.6.1. 2-Chloro-4,6-bis{4-{6-{[1,3-dihydroxy-2-(methyl)prop-2-
yl]amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazin-2-yl}-
piperazin-1-yl}-s-triazine (8a). Yield 75%; white crystalline solid,
conversion of 4e, CHCl
conversion of 4e, EtOH/aq NH
3
/EtOH 1:1), then 6e (2.01 g, 85% partial
25% 9:1).
ꢀ
3
mp 241e242 C (column chromatography, toluene/i-PrOH 2:1).
Found: C, 50.15; H, 6.29; N, 25.44%. C39
C, 50.34; H, 6.50; N, 25.59%; R (66% toluene/i-PrOH) 0.72;
(KBr) 3398, 2926, 2868, 1563, 1537, 1493, 1440, 1364, 1286, 1257,
8
H60ClN17O (929.45) requires
5
.1.4.1. 1-{4,6-Bis{[1-hydroxy-2-(methyl)prop-2-yl]amino}-s-tri-
f
n
max
ꢀ
azin-2-yl}-piperazine (6e). White crystalline solid, mp 156.5e157.4 C
column chromatography, EtOH/aq NH 25% 9:1). Found: C, 52.88; H,
(339.24) requires C, 53.08; H, 8.61; N,
25%) 0.85; max (KBr) 3275, 2968, 2926,
858, 1597, 1554, 1504, 1441, 1363, 1275, 1242, 1200, 1125, 1050, 811,
ꢁ
1
(
3
1229, 1088, 1000, 978, 807, 661 cm
353 K) 1.30 (6H, Me), 1.62 (8H, s, H-6, -10, a.s.), 3.56 (4H, d, J 10.0 Hz,
CH OH), 3.65 (4H, d, J 10.4 Hz, CH OH), 3.76 (24H, s: 8H, H-7, -9, a.s.;
16H, A), 3.94 (8H, s, H-2, -3, a.s.), 4.58 (4H, br s, OH), 5.63 (2H, s, NH)
ppm; (100 MHz, DEPT, DMSO-d , 298 K) 19.2 (Me), 34.9 (C-6, -10,
a.s.), 41.1, 41.4 (C-7, -9, a.s.), 42.8, 43.4 (C-2, -3, -5, -6, A), 58.0 (C-2,
A), 64.3 (C-2, -3, a.s.), 64.7 (CH OH), 107.3 (C-5, a.s.), 164.3 (C-4, -6,
; d (400 MHz, DMSO-d ,
H 6
8
2
2
6
5
.69; N, 29.05%. C15
29 7 2
H N O
8.89%; R (90% EtOH/aq NH
f
3
n
2
2
ꢁ
1
14 cm
;
d
H
(500 MHz, DMSO-d
6
,353 K)1.31(12H,s,Me),2.70(4H,t,J
OH), 3.57 (4H, t,
d
C
6
.0 Hz, H-3, -5, A), 2.95 (1H, br s, ApNH), 3.44(4H, s, CH
2
J 5.0 Hz, H-2, -6, A), 4.65 (2H, br s, OH), 5.45 (2H, s, NH) ppm;
125 MHz, DEPT, DMSO-d , 303 K) 24.4 (Me), 44.4 (C-2, -6, A), 46.0
C-3, -5, A), 54.1 (C-2, D), 69.0 (CH OH), 164.4 (C-2, T-0), 165.6 (C-4, -6,
d
C
2
(
(
6
T-1), 164.6 (C-2, T-0), 165.0 (C-4, T-0), 166.1 (C-6, T-0), 169.3 (C-2, T-
þ
þ
2
1) ppm; m/z (ESI , MeOH in CHCl
3
6:1) 952.6 (MNa ) (0.4), 930.6
þ
T-0) ppm; m/z (DCI positive, 200 eV, i-BuH) 396 (Mþi-BuHꢁ1)
(MH ) (3.5), 703.5 (0.6), 619.6 (3.2), 591.6 (1.0), 465.8 (2.4), 437.2
þ
5
(
(
15), 340 (MH ) (100), 308 (10), 268 (15), 113 (10), 97 (5), 85 (15), 73
(2.1ꢂ10 ).
30%).
5
.1.6.2. 2-Chloro-4,6-bis{4-{6-{[1-hydroxy-2-(hydroxymethyl)
5
K
.1.5. Alternative preparation of compound 7e (Scheme 2). To anhyd
CO (0.56 g, 4.05 mmol) suspended in a dry THF (50 ml) solution
containing anhyd piperazine (0.17 g, 1.97 mmol), compound 4e
1.16 g, 4.00 mmol) was added with vigorous stirring. The reaction
but-2-yl]amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazin-
2-yl}-piperazin-1-yl}-s-triazine (8b). Yield 78%; white crystalline
2
3
ꢀ
solid, mp 236e237 C (crystallisation from EtOH/Et
2
O). Found: C,
(957.48) requires C, 51.38;
(66% toluene/i-PrOH) 0.70; max (KBr) 3400,
2958, 2879, 1566, 1532, 1294, 1439, 1354, 1257, 1228, 1089, 1000,
(
51.55; H, 6.89; N, 25.05%. C41
H, 6.73; N, 24.84%; R
H64ClN17O
8
mixture was heated at reflux for 12 h when TLC monitoring (tolu-
ene/i-PrOH 2:1) showed the formation of 7e as major component of
a mixture containing also the starting 4e and the intermediate 6e.
f
n
ꢁ
1
977, 808, 731, 662 cm
H 6
; d (400 MHz, DMSO-d , 353 K) 0.81 (6H, t,

F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
8963
J 7.2 Hz, CH
.3 Hz, CH CH
0.8 Hz, CH OH), 3.76 (16H, s: 8H, H-7, -9, a.s.; 8H, H-3, -5, A), 3.77
8H, s, H-2, -6, A), 3.93 (8H, s, H-2, -3, a.s.), 4.94 (4H, br s, OH), 5.63
2H, br s, NH) ppm; (100 MHz, DEPT, DMSO-d , 298 K) 8.2
CH CH ), 23.5 (CH CH ), 34.9 (C-6, -10, a.s.), 41.2, 41.6 (C-7, -9, a.s.),
2.9 (C-3, -5, A), 43.4 (C-2, -6, A), 60.5 (C-2, B), 62.5 (C-2, -3, a.s.),
4.3 (CH OH), 107.2 (C-5, a.s.), 164.3 (C-4, -6, T-1), 164.6 (C-2, T-0),
2
CH
3
), 1.62 (8H, t, J 4.8 Hz, H-6, -10, a.s.), 1.83 (4H, q, J
equal portions every 90 min. After each of these periods, TLC
monitoring indicated complete consumption of 8a (toluene/i-PrOH
2:1) and formation of 9a (i-PrOH/aq NH 25%). The reaction mixture
3
was filtered hot and solids were well washed with hot anhyd THF.
The organic filtrate was evaporated under reduced pressure to
dryness and the solid residue was separated by column chroma-
7
1
2
3
), 3.59 (4H, d, J 10.8 Hz, CH
2
OH), 3.65 (4H, d, J
2
(
(
(
4
6
d
C
6
2
3
2
3
3
tography on silica gel (i-PrOH/aq NH 25%) to yield pure product 9a
2
(1.100 g, 78% with respect to 8a).
þ
1
64.9 (C-4, T-0), 165.8 (C-6, T-0), 169.3 (C-2, T-1) ppm; m/z (ESI ,
þ
þ
MeOH) 980.3 (MNa ) (0.05), 958.3 (MH ) (0.90), 619.4 (0.50), 479.7
5.1.7.1. 1-{4,6-Bis{4-{6-{[1,3-dihydroxy-2-(methyl)prop-2-yl]
amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazin-2-yl}-pi-
6
(
0.70), 424.2 (0.25), 371.6 (0.45), 320.5 (0.25), 263.5 (0.50ꢂ10 ).
perazin-1-yl}-s-triazin-2-yl}-piperazine (9a). Yield 78%; yellowish
ꢀ
5.1.6.3. 2-Chloro-4,6-bis{4-{6-{[1,3-dihydroxy-2-(hydroxymethyl)
powder, mp 246e247 C (column chromatography, i-PrOH/aq NH
3
prop-2-yl]amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazin-
25% 9:1). Found: C, 52.45; H, 6.90; N, 27.41%. C43
requires C, 52.69; H, 7.10; N, 27.15%; R (90% i-PrOH/aq NH
0.50; max (KBr) 3414, 2880, 1535m 1485, 1438, 1363, 1255, 1088,
1001, 945, 807, 738, 660 cm
(6H, Me), 1.61 (8H, s, H-6, -10, a.s.), 2.77 (4H, br s, H-3, -5, B) 3.55
(4H, d, J 10.0 Hz, CH OH), 3.65 (4H, d, J 10.0 Hz, CH OH), 3.64e3.74
H
69
N
19
O
8
(979.56)
2
-yl}-piperazin-1-yl}-s-triazine (8c). Yield 86%; white crystalline
f
3
25%)
ꢀ
solid, mp 248.2e249.4 C (crystallisation from THF). Found: C,
n
ꢁ1
4
4
3
8.84; H, 6.09; N, 25.01%. C39
8.67; H, 6.28; N, 24.74%; R (66% toluene/i-PrOH) 0.40;
387, 2934, 2879, 1564, 1492, 1439, 1364, 1286, 1257, 1229, 1113,
H
60ClN17
O
10 (961.44) requires C,
H 6
; d (400 MHz, DMSO-d , 353 K) 1.30
f
n
max (KBr)
2
2
ꢁ
1
1
085, 999, 977, 806, 661 cm
8H, br t, H-6, -10, a.s.), 3.72 (28H, s: 12H, CH
t, J 5.6 Hz, H-7, -9, a.s.), 3.93 (8H, s, H-2, -3, a.s.), 4.10 (6H, br s, OH),
.69 (2H, br s, NH) ppm; (100 MHz, DEPT, DMSO-d , 298 K) 34.9
C-6, -10, a.s.), 41.2, 41.7 (C-7, -9, a.s.), 43.0 (C-3, -5, A), 43.4 (C-2, -6,
A), 61.2 (C-2, -3, a.s.), 61.7 (C-2, C), 64.3 (CH OH), 107.2 (C-5, a.s.),
;
d
H
(400 MHz, DMSO-d
6
, 353 K) 1.63
(28H, br m: 8H, H-7, -9, a.s.; 16H, A; 4H, H-2, -6, B), 3.80 (5H, br s:
4H, OH; 1H, BpNH), 3.93 (8H, s, H-2, -3, a.s.), 5.59 (2H, s, NH) ppm;
(
2
OH; 16H, A), 3.76 (8H,
d
C
(100 MHz, DEPT, DMSO-d
41.1, 41.4 (C-7, -9, a.s.), 43.1, 43.2 (CH
-5, B), 58.0 (C-2, A), 64.3 (C-2, -3, a.s.), 64.7 (CH
6
, 298 K) 19.2 (Me), 34.9 (C-6, -10, a.s.),
, A), 43.8 (C-2, -6, B), 45.6 (C-3,
OH),107.3 (C-5, a.s.),
5
(
d
C
6
2
2
2
164.5 (C-2, T-0), 165.0 (C-4, T-0), 165.1 (C-2, T-1), 165.2 (C-4, -6, T-1),
þ
1
64.4 (C-4, -6, T-1), 164.8 (C-2, -4, T-0), 165.7 (C-6, T-0), 169.3 (C-2,
166.1 (C-6, T-0) ppm; m/z (ESI in MeOH diluted with CHCl
3
/MeOH
þ
þ
þ
T-1) ppm; m/z (ESI , ACN/H
2
O): HRMS calcd for C39
61
H N
17
O
10
6:1) 1002.7 (MNa ) (0.2), 980.8 (MH ) (6.0), 647.6 (3.6), 619.6 (4.2),
591.6 (1.4), 490.9 (2.2), 437.2 (1.4ꢂ10 ).
þ
5
(
MH ) 962.4476; found 962.4496 (100%).
5
.1.6.4. 2-Chloro-4,6-bis{4-{6-{[1-hydroxy-2-(methyl)prop-2-yl]
5.1.7.2. 1-{4,6-Bis{4-{6-{[1-hydroxy-2-(hydroxymethyl)but-2-yl]
amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazin-2-yl}-pi-
amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazin-2-yl}-pi-
perazin-1-yl}-s-triazine (8d). Yield 68%; white crystalline solid, mp
perazin-1-yl}-s-triazin-2-yl}-piperazine (9b). Yield 85%; yellowish
ꢀ
ꢀ
2
44.8e246.1 C (column chromatography, AcOEt/Ligroin 16:1).
powder, mp 243e244 C (column chromatography, i-PrOH/aq NH
3
Found: C, 51.94; H, 6.45; N, 26.55%. C39
C, 52.14; H, 6.73; N, 26.50%; R (94% AcOEt/Ligroin) 0.67;
350, 2958, 1544, 1489, 1438, 1362, 1256, 1226, 1090, 1002, 978, 941,
H
60ClN17
O
6
(897.46) requires
25% 9:1). Found: C, 53.83; H, 7.56; N, 26.65%. C45
requires C, 53.61; H, 7.30; N, 26.40%; R (90% i-PrOH/aq NH
0.48; max (KBr) 3400, 2963, 1530, 1485, 1434, 1364, 1285, 1254,
1115, 1088, 1000, 945, 807, 739, 661 cm
353 K) 0.80 (6H, t, J 7.4 Hz, CH CH ), 1.61 (8H, t, J 5.6 Hz, H-6, -10,
a.s.), 1.84 (4H, q, J 7.3 Hz, CH CH ), 2.82 (4H, t, J 5.0 Hz, H-3, -5, B),
3.58 (4H, d, J 10.8 Hz, CH OH), 3.64 (4H, d, J 10.4 Hz, CH OH),
H
73
N
19
O
8
(1007.59)
f
nmax (KBr)
f
3
25%)
3
8
n
ꢁ
1
ꢁ1
; d
08, 661 cm
;
d
H
(500 MHz, DMSO-d
6
, 363 K) 1.33 (12H, s, Me),
OH), 3.77 (8H, t, J
.0 Hz, H-7, -9, a.s.; 16H, s, A), 3.93 (8H, s, H-2, -3, a.s.), 4.65 (2H, br s,
OH), 5.66 (2H, br s, NH) ppm; (125 MHz, DEPT, DMSO-d , 298 K)
4.3 (Me), 34.9 (C-6, -10, a.s.), 41.0, 41.4 (C-7, -9, a.s.), 42.8 (C-3, -5,
A), 43.4 (C-2, -6, A), 54.3 (C-2, D), 64.3 (C-2, -3, a.s.), 68.7 (CH OH),
07.3 (C-5, a.s.), 164.3 (C-4, -6, T-1), 164.6 (C-2, T-0), 165.0 (C-4, T-0),
H 6
(400 MHz, DMSO-d ,
1.62 (8H, t, J 5.8 Hz, H-6, -10, a.s.), 3.48 (4H, s, CH
2
2
3
5
2
3
d
C
6
2
2
2
3.69e3.76 (29H, m: 8H, H-7, -9, a.s.; 16H, A; 4H, H-2, -6, B; 1H,
BpNH), 3.93 (8H, s, H-2, -3, a.s.), 4.58 (4H, br s, OH), 5.49 (2H, s, NH)
2
1
ppm;
23.5 (CH
(CH , A), 43.4 (C-2, -6, B), 45.3 (C-3, -5, B), 60.4 (C-2, B), 62.6 (C-2, -3,
a.s.), 64.3 (CH OH), 107.3 (C-5, a.s.), 164.5, 164.6 (C-2, T-0),
165.06 (C-4, T-0), 165.15 (C-2, T-1), 165.24 (C-4, -6, T-1), 166.0 (C-6,
d
C
6 2 3
(100 MHz, DEPT, DMSO-d , 298 K) 8.3 (CH CH ),
þ
1
66.0 (C-6, T-0), 169.3 (C-2, T-1) ppm; m/z (ESI , ACN in DCM) 936.5
2
CH ), 34.9 (C-6, -10, a.s.), 41.0, 41.6 (C-7, -9, a.s.), 43.0
3
þ
þ
þ
6
(
MK ) (1.0), 920.5 (MNa ) (0.5), 898.5 (MH ) (5.3ꢂ10 ).
2
2
5
.1.6.5. 2-Chloro-4,6-bis{4-{4,6-bis{[1-hydroxy-2-(methyl)prop-
þ
þ
þ
2
-yl]amino}-s-triazin-2-yl}piperazin-1-yl}-s-triazine (8e). Yield 90%;
T-0) ppm; m/z (ESI in MeOH) 1030.4 (MNa ) (0.02), 1008.4 (MH )
ꢀ
white crystalline solid, mp 220e222 C (crystallisation from EtOH/
(1.2), 504.7 (2.4), 447.7 (0.6), 413.2 (1.4), 339.6 (0.5), 288.6
6
Et
requires C, 50.15; H, 7.14; N, 30.13%; R
max (KBr) 3398, 2967, 2924, 2865, 1566, 1494, 1440, 1361, 1274,
2
O). Found: C, 50.35; H, 6.88; N, 30.31%. C33
H56ClN17
O
4
(789.44)
(1.4ꢂ10 ).
f
(66% toluene/i-PrOH) 0.75;
n
5.1.7.3. 1-{4,6-Bis{4-{6-{[1,3-dihydroxy-2-(hydroxymethyl)prop-
2-yl]amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazin-2-yl}-
piperazin-1-yl}-s-triazin-2-yl}-piperazine (9c). Yield 73%; yellowish
ꢁ
1
1
229, 1169, 1057, 998, 977, 811, 740, 502 cm
, 353 K) 1.34 (24H, s, Me), 3.47 (8H, s, CH
A), 4.77 (4H, br s, OH), 5.58 (4H, s, NH) ppm;
DMSO-d , 303 K) 24.4 (Me), 42.8 (C-3, -5, A), 43.1, 43.4 (C-2, -6, A),
4.2 (C-2, D), 69.0 (CH
.
d
H
(500 MHz, DMSO-
OH), 3.71e3.83 (16H, m,
(125 MHz, DEPT,
d
6
2
ꢀ
d
C
powder, mp 256e257.4 C (column chromatography, i-PrOH/aq
6
NH
3
25% 4:1). Found: C, 50.89; H, 7.03; N, 26.25%. C43
69 19 10
H N O
5
1
2
OH), 164.4 (C-4, -6, T-1), 164.5 (C-2, T-0),
65.7 (C-4, -6, T-0), 169.3 (C-2, T-1) ppm; m/z (ESI , acetone/DMSO
(1011.55) requires C, 51.03; H, 6.87; N, 26.29%; R
f
(80% i-PrOH/aq
þ
NH
3
25%) 0.42;
n
max (KBr) 3408, 2931, 2880, 1531, 1480, 1436, 1364,
þ
ꢁ1
diluted with ACN) 790 (MH ) (3.6), 639.5 (0.5), 595.4 (0.6), 551.4
1284, 1254, 1111, 1085, 1000, 944, 806, 740, 661 cm
DMSO-d
.0 Hz, H-3, -5, B), 3.72 (12H, s, CH
7, -9, a.s.; 16H, A; 4H, H-2, -6, B; 1H, BpNH), 3.93 (8H, s, H-2, -3, a.s.),
4.54 (6H, br s, OH), 5.55 (2H, s, NH) ppm; (125 MHz, DEPT,
DMSO-d , 298 K) 34.9 (C-6, -10, a.s.), 41.1, 41.6 (C-7, -9, a.s.), 42.9,
43.0 (CH , A), 43.2 (C-2, -6, B), 45.0 (C-3, -5, B), 61.3 (C-2, -3, a.s.),
61.6 (C-2, C), 64.3 (CH OH), 107.2 (C-5, a.s.), 164.5 (C-2, T-0), 164.9
H
; d (500 MHz,
5
(
0.5), 507.4 (0.4), 463.3 (0.2), 413.3 (0.2ꢂ10 ).
6
, 363 K) 1.62 (8H, t, J 5.8 Hz, H-6, -10, a.s.), 2.87 (4H, t, J
OH), 3.69e3.76 (29H, m: 8H, H-
5
2
5
.1.7. Typical procedure for the synthesis of compounds 9aee. Prep-
aration of compound 9a (Scheme 3). To anhyd K CO (0.198 g,
.438 mmol) suspended a dry THF (125 mL) boiling solution con-
taining anhyd piperazine (0.495 g, 5.75 mmol), compound 8a
1.336 g, 1.438 mmol) was added, with vigorous stirring, as five
2
3
d
C
1
6
2
(
2

8964
F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
(
C-4, T-0), 165.1 (C-2, T-1), 165.2 (C-4, -6, T-1), 166.1 (C-6, T-0) ppm;
EtOH) 0.60;
1256, 1087, 998, 807, 740, 661 cm
n
max (KBr) 3394, 2925, 2878, 1537, 1484, 1435, 1363,
þ
þ
ꢁ1
m/z (ESI , ACN diluted with DCM/DMSO 3:1) 1012.6 (MH )
H 6
; d (400 MHz, DMSO-d , 353 K)
7
(
2.25ꢂ10 ).
1.30 (12H, Me), 1.61 (16H, s, H-6, -10, a.s.), 3.56 (8H, d, J 10.0 Hz,
CH OH), 3.66 (8H, d, J 10.4 Hz, CH OH), 3.72e3.79 (64H, br m: 32H,
A; 16H, B; 16H, H-7, -9, a.s.), 3.93 (16H, s, H-2, -3, a.s.), 4.60 (8H, br s,
OH), 5.60 (4H, s, NH) ppm; (100 MHz, DEPT and QC, DMSO-d
2
2
5
.1.7.4. 1-{4,6-Bis{4-{6-{[1-hydroxy-2-(methyl)prop-2-yl]
amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazin-2-yl}-pi-
d
C
6
,
perazin-1-yl}-s-triazin-2-yl}-piperazine (9d). Yield 80%; yellowish
powder, mp 254.2e255 C (column chromatography, i-PrOH/aq
298 K) 19.3 (4C, Me), 34.9 (8C, C-6, -10, a.s.), 41.1 (8C, C-7, -9, a.s.),
43.1 (20C: 16C, A; 4C, C-3, -5, B), 43.5 (4C, C-2, -6, B), 58.0 (4C, C-2,
ꢀ
NH
947.57) requires C, 54.47; H, 7.34; N, 28.07%; R
NH 25%) 0.53; max (KBr) 3300, 2958, 2925, 1536, 1489, 1438,
363, 1254, 1117, 997, 944, 810, 743 cm
3
25% 9:1). Found: C, 54.57; H, 7.29; N, 27.85%. C43
H
69
N
19
O
6
2
A), 64.3 (8C, C-2, -3, a.s.), 64.8 (8C, CH OH), 107.3 (4C, C-5, a.s.),
164.4 (2C, C-4, -6, T-2), 164.6 (4C, C-2, T-0), 165.0 (4C, C-4, T-0),
(
f
(90% i-PrOH/aq
3
n
165.2 (6C, T-1), 166.1 (4C, C-6, T-0), 169.4 (1C, C-2, T-2) ppm; m/z
ꢁ
1
þ
þ
þ
1
;
d
H
(500 MHz, DMSO-d
63 K) 1.33 (12H, s, Me), 1.61 (8H, t, J 5.5 Hz, H-6, -10, a.s.), 2.98
OH), 3.71e3.77 (25H,
m: 8H, H-7, -9, a.s.; 16H, A; 1H, BpNH), 3.84 (4H, t, J 5.0 Hz, H-2,
6, B), 3.93 (8H, s, H-2, -3, a.s.), 4.66 (2H, br s, OH), 5.62 (2H, s,
NH) ppm; (125 MHz, DEPT, DMSO-d , 298 K) 24.3 (Me), 34.9
C-6, -10, a.s.), 41.0, 41.1, 41.4, 41.6 (C-7, -9, a.s.), 43.1 (CH , A; C-2,
6, B), 44.1 (C-3, -5, B), 54.3 (C-2, D), 64.3 (C-2, -3, a.s.), 68.7
6
,
(ESI in MeOH) 2092.6 (MNa ) (1.6), 2071.7 (MH ) (2.5), 1215.6
4
3
(1.4), 1036.4 (0.6), 913.7 (0.4ꢂ10 ).
(
4H, t, J 5.0 Hz, H-3, -5, B), 3.48 (4H, s, CH
2
5.1.8.2. 2-Chloro-4,6-bis{4-{4,6-bis{4-{6-{[1-hydroxy-2-(hydrox-
ymethyl)but-2-yl]amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-
triazin-2-yl}-piperazin-1-yl}-s-triazin-2-yl}-piperazin-1yl}-s-triazine
-
d
C
6
(
2
(10b). Yield 91% (crystallisation from i-PrOH), 78% (column chro-
ꢀ
-
matography, CHCl
Found: C, 52.65; H, 6.98; N, 27.11%. C93
quires C, 52.49; H, 6.82; N, 26.99%; R (87.5% CHCl
3
/EtOH 7:1) yellowish powder, mp 254e255 C.
(
(
CH
2
OH), 107.3 (C-5, a.s.), 164.6 (C-2, T-0), 165.1 (C-4, T-0), 165.15
H144ClN41
O
16 (2126.14) re-
þ
C-2, T-1), 165.21 (C-4, -6, T-1), 166.0 (C-6, T-0) ppm; m/z (ESI ,
f
3
/EtOH) 0.56;
n
max
þ
þ
þ
ACN in DCM) 986.6 (MK ) (0.1), 970.6 (MNa ) (0.1), 948.6 (MH )
(
(KBr) 3410, 2959, 2924, 2879, 1535, 1485, 1435, 1363, 1287, 1257,
7
ꢁ1
3.5ꢂ10 ).
1089, 998, 807, 661 cm
H 6
; d (500 MHz, DMSO-d , 353 K) 0.81
(
12H, br s, CH
7.7 Hz, CH CH
11.0 Hz, CH
(16H, br s, B), 3.93 (16H, s, H-2, -3, a.s.), 4.59 (8H, br s, OH), 5.50 (4H,
s, NH) ppm; (125 MHz, DEPT and QC, DMSO-d , 298 K) 8.22 (4C,
CH CH ), 23.5 (4C, CH CH ) 34.9 (8C, C-6, -10, a.s.), 41.0, 41.6 (8C, C-
7, -9, a.s.), 43.1 (20C: 16C, A; 4C, C-3, -5, B), 43.4 (4C, C-2, -6, B), 60.3
(4C, C-2, B), 62.6 (8C, C-2, -3, a.s.), 64.3 (8C, CH OH), 107.2 (4C, C-5,
2
CH
3
), 1.61 (16H, br s, H-6, -10, a.s.), 1.83 (8H, br q, J
5
.1.7.5. 1-{4,6-Bis{4-{4,6-bis{[1-hydroxy-2-(methyl)prop-2-yl]
2
3
), 3.59 (8H, br d, J 9.5 Hz, CH
2
OH), 3.65 (8H, br d, J
amino}-s-triazin-2-yl}-piperazin-1-yl}-s-triazin-2-yl}-piperazine
2
OH), 3.71 (16H, br s, H-7, -9, a.s.), 3.76 (32H, br s, A), 3.79
ꢀ
(
9e). Yield 70%; white powder, mp 225e230 C (column chroma-
tography, EtOH/aq NH
(839.55) requires C, 52.90; H, 7.80; N, 31.68%; R
25%) 0.30; max (KBr) 3385, 3330, 2968, 2924, 1543,
3
25% 9:1). Found: C, 53.11; H, 8.09; N, 31.59%.
d
C
6
C
37
65
H N
19
O
4
f
(90%
2
3
2
3
EtOH/aq NH
3
n
ꢁ
1
1
484, 1438, 1359, 1271, 1198, 1054, 999, 809 cm
;
d
H
(500 MHz,
, 353 K) 1.34 (24H, s, Me), 2.85 (4H, t, J 5.0 Hz, H-3, -5, B),
OH), 3.69e3.71 (13H, m: 8H, H-2, -6, A; 4H, OH; 1H,
BpNH), 3.74e3.77 (12H, m: 4H, t, J 5.0, H-2, -6, B; 8H, H-3, -5, A),
.53 (4H, s, NH) ppm; (125 MHz, DEPT, DMSO-d , 303 K) 24.4
Me), 42.98 (CH , A), 43.05 (C-2, -6, B), 45.0 (C-3, -5, B), 54.2 (C-2, D),
OH), 164.6 (C-2, T-0), 165.2 (C-2, T-1), 165.3 (C-4, -6, T-1),
2
DMSO-d
3
6
a.s.), 164.3 (2C, C-4, -6, T-2), 164.47, 164.50, 164.56, 164.59, 164.64,
164.68, 164.73 (4C, C-2, T-0), 165.0 (4C, C-4, T-0), 165.20, 165.24 (6C,
.46 (8H, s, CH
2
þ
T-1), 166.0 (4C, C-6, T-0), 169.3 (1C, C-2, T-2) ppm; m/z (ESI in
þ
5
(
6
d
C
6
MeOH) 2127.7 (MH ) (0.40), 1564.4 (0.4), 1542.4 (0.65), 619.4
5
2
(0.85ꢂ10 ).
9.0 (CH
2
þ
þ
1
65.7 (C-4, -6, T-0) ppm; m/z (ESI in MeOH) 862.4 (MNa ) (0.8),
5.1.8.3. 2-Chloro-4,6-bis{4-{4,6-bis{4-{6-{[1,3-dihydroxy-2-(hy-
droxymethyl)prop-2-yl]amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-
yl)-s-triazin-2-yl}-piperazin-1-yl}-s-triazin-2-yl}-piperazin-1-yl}-s-
þ
8
40.5 (MH ) (4.8), 809.5 (0.2), 768.4 (0.4), 696.3 (0.5), 624.2 (0.5),
6
5
52.2 (0.6), 413.2 (0.3), 276.5 (1.0ꢂ10 ).
ꢀ
triazine (10c). Yield 56%; yellowish powder, mp 264e265 C (col-
5
.1.8. Typical procedure for the synthesis of compounds 10aee.
umn chromatography, eluent CHCl
H, 6.33; N, 27.05%. C89 20 (2134.06) requires C, 50.05; H,
6.42; N, 26.89%; R (77.7% CHCl /EtOH) 0.66; max (KBr) 3391, 2925,
2878, 1536, 1483, 1435, 1363, 1257, 1111, 1085, 997, 807, 737 cm
(500 MHz, DMSO-d , 363 K) 1.63 (16H, t, J 5.3 Hz, H-6, -10, a.s.),
3.73 (24H, d, J 5.0 Hz, CH OH), 3.76 (64H, t, J 5.8 Hz: 16H, H-7, -9,
a.s.; 32H, A; 8H, H-3, -5, B), 3.80 (8H, s, H-2, -6, B), 3.93 (16H, s, H-2,
-3, a.s.), 4.51 (12H, t, J 5.3 Hz, OH), 5.56 (4H, s, NH) ppm;
(125 MHz, DEPT and QC as 5 mM in DMSO-d , 298 K) 34.9 (4C, C-6,
-10, a.s.), 41.1, 41.6 (8C, C-7, -9, a.s.), 42.8, 43.0 (16C, A), 43.3, (4C, C-3,
-5, B), 43.5 (4C, C-2, -6, B), 61.2, 61.3 (12C, CH OH), 61.5, 61.6 (8C, C-
3
/EtOH 3.5:1). Found: C, 49.81;
Preparation of compound 10b (Scheme 3). To anhyd K
0
solution containing compound 9b (0.700 g, 0.694 mmol), cyanuric
chloride (0.061 g, 0.331 mmol) as THF (3 mL) solution was injected
slowly, under vigorous stirring. The reaction mixture was allowed
to reach room temperature overnight and then heated at reflux for
2
CO
3
(0.100 g,
H136ClN41O
ꢀ
.725 mmol) suspended in dry and cooled (ꢁ10 C) THF (35 mL)
f
3
n
ꢁ
1
;
d
H
6
2
1
6 h. Since the TLC monitoring (CHCl
presence of the unreacted 9b, THF was replaced by 1,4-dioxane
35 mL) and refluxing was continued for an additional 6 h (TLC
3
/i-PrOH 7:1) still indicated the
d
C
6
(
monitoring). The reaction mixture was evaporated under reduced
pressure to dryness and the solid residue taken, at room temper-
ature, with cooled water (6 mL) under vigorous stirring, filtered and
washed with cooled water to neutrality. After drying at 80 C to
constant mass, the crude product was twice crystallised from
2
2, C), 64.3 (8C, C-2, -3, a.s.),107.2 (4C, C-5, a.s.),164.36 (2C, C-4, -6, T-
2), 164.41, 164.43, 164.47, 164.54 (4C, C-2, T-0), 164.9 (4C, C-4, T-0),
165.2, 165.3 (6C, T-1), 166.1 (4C, C-6, T-0), 169.3 (1C, C-2, T-2) ppm;
ꢀ
þ
þ
m/z (ESI , CAN diluted with DCM/DMSO) 2174.0 (Mþ1þK ) (0.4),
þ
minimum amount of boiling isopropanol to yield pure 10b (0.640 g,
2157.9 (Mþ1þNa ) (0.4), 2135.9 (Mþ2) (2.9), 1351.8 (1.9), 1140.7
4
91% yield with respect to cyanuric chloride).
(1.8) 1043.7 (6.7ꢂ10 ).
5
.1.8.1. 2-Chloro-4,6-bis{4-{4,6-bis{4-{6-{[1,3-dihydroxy-2-
5.1.8.4. 2-Chloro-4,6-bis{4-{4,6-bis{4-{6-{[1-hydroxy-2-(methyl)
prop-2-yl]amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazin-
2-yl}-piperazin-1-yl}-s-triazin-2-yl}-piperazin-1-yl}-s-triazine
(
methyl)prop-2-yl]amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-
s-triazin-2-yl}-piperazin-1-yl}-s-triazin-2-yl}-piperazin-1yl}-s-tri-
azine (10a). Yield 87% (crystallisation from i-PrOH), 73% (column
ꢀ
(10d). Yield 98%; yellowish powder, mp 265e275 C (dec); (crys-
chromatography, CHCl
3
/EtOH 7:1) yellowish powder, mp
tallisation from EtOH). Found: C, 52.98; H, 7.01; N, 28.55%.
ꢀ
2
55e256 C. Found: C, 51.49; H, 6.81; N, 27.54%. C89
H
136
N
41
C
89
H136ClN41
O
12 (2006.1) requires C, 53.24; H, 6.83; N, 28.60%; R
f
(
2070.08) requires C, 51.60; H, 6.62; N, 27.72%; R
f
(87.5% CHCl
3
/
(91% CHCl
3
/i-PrOH) 0.46; max (KBr) 3400, 2964, 2925, 2870, 1533,
n

F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
8965
ꢁ1
1
490, 1436, 1364, 1255, 1088, 997, 807, 737 cmꢁ1;
DMSO-d , 363 K) 1.34 (24H, s, Me), 1.61 (16H, J 5.5 Hz, H-6, -10, a.s.),
.48 (8H, d, J 5.5 Hz, CH OH), 3.72 (32H, t, J 5.0 Hz: 16H, H-7, -9, a.s.;
6H, A), 3.77 (24H, t, J 5.5 Hz: 16H, A; 8H, H-3, -5, B), 3.80 (8H, s, H-2,
6, B), 3.93 (16H, s, H-2, -3, a.s.), 4.68 (4H, t, J 5.5 Hz, OH), 5.64 (4H, s,
NH) ppm; (125 MHz, DEPT and QC as 5 mM in DMSO-d , 298 K)
4.4 (8C, Me), 34.9 (8C, C-6, -10, a.s.), 41.0, 41.4 (8C, C-7, -9, a.s.), 43.1
20C: 16C, A; 4C, C-3, -5, B), 43.5 (4C, C-2, -6, B), 54.3 (4C, C-2, D),
4.3 (8C, C-2, -3, a.s.), 68.7 (4C, CH OH), 107.3 (4C, C-5, a.s.), 164.4
2C, C-4, -6, T-2), 164.6 (4C, C-2, T-0), 165.1 (4C, C-4, T-0), 165.2,
65.3 (6C, T-1), 166.0 (4C, C-6, T-0), 169.3 (1C, C-2, T-2) ppm; m/z
d
H
(500 MHz,
1652, 1608, 1536, 1483, 1437, 1362, 1255, 1114, 997, 805, 779 cm
(500 MHz, DMSO-d , 353 K) 1.30 (24H, s, Me), 1.61 (32H, t, J
;
6
d
H
6
0
0
3
1
-
2
5.5 Hz, H-6, -10, a.s.), 1.51e1.54, 1.70e1.72 (10H, m, H-3, -3 -4, -4
0
-5, -5 , bip.), 3.56 (16H, d, J 9.0 Hz, CH
2
OH), 3.65 (16H, d, J 9.5 Hz,
CH
2
OH), 3.72e3.77 (136H, m: 64H, A; 32H, B; 32H, H-7, -9, a.s.; 8H,
0
0
d
C
6
H-2, -2 , -6, -6 , bip.), 3.93 (32H, s, H-2, -3, a.s.), 4.58 (16H, br s, OH),
2
(
6
(
5.59 (8H, s, NH) ppm;
d
C
(100 MHz, DEPT and QC as 5 mM in DMSO-
0
d
6
, 298 K) 19.2 (8C, Me), 34.9 (20C: 16C, C-6, -10, a.s.; 4C, C-3, -3 , -5,
0
0
0
0
2
-5 , bip.), 41.1, 41.4 (22C: 16C, C-7, -9, a.s.; 6C, C-1, -1 , C-2, -2 , -6, -6 ,
bip.), 43.1 (48C: 32C, A; 16C, B), 58.0 (8C, C-2, A), 64.3 (16C, C-2, -3,
a.s.), 64.7 (16C, CH OH), 107.2 (8C, C-5, a.s.), 164.5 (8C, C-2, T-0),
2
165.0 (10C: 8C, C-4, T-0; 2C, T-2); 165.2 (14C: 12C, C-2, -4, -6, T-1;
1
þ
þ
þ
(
(
ESI , ACN diluted with DCM) 2046.0 (MK ) (0.80), 2030.0 (MNa )
þ
5
1.45), 2008.0 (MH ) (1.55ꢂ10 ).
2C, T-2), 166.1 (10C: 8C, C-6, T-0; 2C, T-2); m/z (linear MALDIþ,
þ
matrix 2,6-dihydroxybenzoic acid) 4237.132 (MH ) (4200 a.u.).
5
.1.8.5. 2-Chloro-4,6-bis{4-{4,6-bis{4-{4,6-bis{[1-hydroxy-2-
0
(
methyl)prop-2-yl]amino}-s-triazin-2-yl}-piperazin-1-yl}-s-triazin-
5.1.9.2. 1,1 -{4,6-Bis{4-{4,6-bis{4-{6-{[1-hydroxy-2-(hydrox-
2
-yl}-piperazin-1yl}-s-triazine (10e). Yield 70% (crystallisation from
ymethyl)but-2-yl]amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-
triazin-2-yl}-piperazin-1-yl}-s-triazin-2-yl}-piperazin-1yl}-s-tri-
azine-2-yl}-4,4 -bipiperidine (11b). Yield 69% (trituration from DMF/
ꢀ
EtOH) white powder, mp 260e270 C (dec), 63% (column chroma-
tography, CHCl
C
3
0
3
/EtOH 5:1). Found: C51.88; H: 6.91; N: 32.29%.
(1790.06) requires: C, 51.62; H, 7.20; Cl, 1.98; N,
H128ClN41O
77 8
2 3 2
Et O 1:3), 68% (column chromatography: CHCl /EtOH/Et O 3:1:1 to
2.05%; R
f
3
(83% CHCl /EtOH) 0.75;
n
max (KBr) 3402, 2970, 2926, 2863,
elute precursor 10b then CHCl
mp 260e261 C. Found: C, 53.97; H, 6.89; N, 27.19%. C196
3
/EtOH 3:1 to elute 11b) white powder,
ꢁ
1
ꢀ
1
547, 1484, 1437, 1361, 1265,1232,1199, 1177, 1056, 998, 809 cm
500 MHz, DMSO-d , 353 K) 1.33 (48H, s, Me), 3.47 (16H, d J 4.0 Hz,
CH OH), 3.71e3.72 (16H, m, piperazine A), 3.75e3.77 (24H, m: 16H,
A; 8H, H-3, -5, B), 3.80 (8H, s, H-2, -6, B), 4.76 (8H, t, J 5.5 Hz, OH), 5.53
.
d
H
H N O
306 84 32
(
6
(4348.49) requires C, 54.10; H, 7.09; N, 27.04%; R
f
3
(75% CHCl /EtOH)
2
0.75;
1089, 999, 806, 661 cm
t, J 7.5 Hz, CH CH
-4 , -5, -5 , bip.),1.83 (16H, q, J 7.2 Hz, CH
CH OH), 3.64 (16H, d, J 9.5 Hz, CH OH), 3.70e3.75 (136H, m: 64H, A;
32H, B; 32H, H-7, -9, a.s.; 8H, H-2, -2 , -6, -6 , bip.), 3.92 (32H, s, H-2,
-3, a.s.), 4.59 (16H, br s, OH), 5.50 (8H, s, NH) ppm; (100 MHz, DEPT
and QC as 5 mM in DMSO-d , 298 K) 8.3 (8C, CH
CH CH
nmax (KBr) 3402, 2931, 2878, 1671, 1534, 1483, 1435, 1364, 1254,
ꢁ
1
;
d
H
(500 MHz, DMSO-d
6
, 353 K) 0.80 (24H,
0
(
(
1
1
8H, s, NH) ppm;
16C, Me), 43.1 (24C: 16C, A; 8C, B), 54.2 (8C, C-2, D), 69.0 (8C, CH
64.3 (2C, C-4, -6, T-2), 164.5 (4C, C-2, T-0), 165.2 (4C, C-4, -6, T-1),
65.7 (8C, C-4, -6, T-0), 165.9 (2C, C-2, T-1), 169.3 (1C, C-2, T-2); m/z
d
C
6
(100 MHz, DEPT and QC, DMSO-d , 298 K) 24.4
2
3
),1.61 (42H, br s: 32H, H-6, -10, a.s.; 10H, H-3, -3 -4,
0
0
2
OH),
2 3
CH ), 3.58 (16H, d, J 10.5 Hz,
2
2
0
0
þ
þ
(
ESI , acetone-DMSO diluted with ACN) 1829.2 (MK ) (0.5), 1814.2
d
C
þ
þ
4
(
MNa ) (1.1), 1791.3 (MH ) (2.1ꢂ10 ).
6
2
CH
3
), 23.5 (8C,
0
0
2
3
), 35.0 (20C: 16C, C-6, -10, a.s.; 4C, C-3, -3 , -5, -5 , bip.), 41.6
(22C: 16C, C-7, -9, a.s.; 6C, C-1, -1 , C-2, -2 , -6, -6 , bip.), 43.1 (48C: 32C,
A; 16C, B), 60.4 (8C, C-2, B), 62.5 (16C, C-2, -3, a.s.), 64.3 (16C, CH OH),
0
0
0
5.1.9. Typical procedure for the synthesis of compounds 11a, 11b, 11d
and 11e. Preparation of compound 11b (Scheme 3). G-2 dendron 10b
2
(
dried under high vacuum to constant mass then analytically
107.3 (8C, C-5, a.s.),164.5,164.7 (8C, C-2, T-0),165.1 (10C: 8C, C-4, T-0;
2C, T-2); 165.3 (14C: 12C, C-2, -4, -6, T-1; 2C, T-2),166.0 (10C: 8C, C-6,
T-0; 2C, T-2); m/z (linear MALDIþ, matrix 2,6-dihydroxybenzoic acid)
0
weighted 0.515 g, 0.242 mmol), freshly prepared 4,4 -bipiperidine
(
weighted 0.0193 g, 0.115 mmol), potassium carbonate (analytically
weighted 0.035 g, 0.254 mmol) and freshly distilled dime-
thylformamide (DMF) (25 mL) were mixed together and the
dried under high vacuum to constant mass then analytically
þ
4348.4 (M ) (100), 4247.0 (17), 3764.4 (27), 3098.9 (12),1800.7 (18%).
0
5.1.9.3. 1,1 -{4,6-Bis{4-{4,6-bis{4-{6-{[1-hydroxy-2-(methyl)
ꢀ
resulting suspension was heated at 100 C (CARE! Avoid refluxing
prop-2-yl]amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazin-
DMF to prevent solvent decomposition!) for 36 h (TLC monitoring,
2-yl}-piperazin-1-yl}-s-triazin-2-yl}-piperazin-1yl}-s-triazine-2-yl}-
0
CHCl
3
/EtOH 3:1 v/v). DMF was distilled under reduced pressure and
4,4 -bipiperidine (11d). Yield 48% (column chromatography: CHCl
3
/
the solid residue was taken with distilled water (10 mL), stirred at
room temperature for 30 min then filtered off. The crude product
was well washed with distilled water (ꢂ5 mL) to neutrality then
EtOH/Et
2
O 3:0.5:1.5 to elute precursor 10d then CHCl
3
/EtOH 3:0.5 to
ꢀ
elute 11d); grey powder, mp 272e282 C (dec). Found: C, 55.15; H,
6.95; N, 28.81%. C188
28.62; R (86% CHCl
1483, 1436, 1363, 1254, 1176, 1086, 994, 947, 810, 754, 659 cm
(500 MHz, DMSO-d , 353 K) 1.32 (48H, s, Me),1.60 (42H, br s: 32H, H-
6, -10 a.s.; 10H, H-3, -3 -4, -4 -5, -5 , bip.), 3.47 (16H, br s, CH
290 84
H N O24 (4108.41) requires C, 54.93; H, 7.11; N,
ꢀ
dried at 70 C to constant weight. The crude product was dissolved
f
3
/EtOH) 0.52; max (KBr) 3300, 2925, 2864, 1536,
n
ꢁ1
in distilled DMF (2 mL), then crystallised by adding anhyd diethyl
; d
H
ꢀ
ether (6 mL). The resulted suspension was cooled at ꢁ20 C for
6
0
0
0
2
4 h, filtered off and well washed with anhyd diethyl ether to af-
2
OH),
ꢀ
0
ford, after drying at 70 C to constant weight, 0.345 g compound
3.71e3.75(136H, bm: 64H, A; 32H, B; 32H, H-7, -9, a.s.;8H, H-2, -2 , -6,
0
0
11b (69% yield with respect to 4,4 bipiperidine). Alternative iso-
-6 , bip.), 3.91 (32H, s, H-2, -3, a.s.), 4.70 (8H, br s, OH), 5.64 (8H, br s,
lation by column chromatography: the crude and dried product
was first eluted on silica gel with CHCl /EtOH/Et O 3:1:1 to recover
.041 g (0.019 mmol, 8%) unreacted chlorodendron 10b. With the
NH);
a.s.; C-3, -3 , -5, 5 , bip.), 41.0 (C-7, -9, a.s.; C-2, -2 , -6, -6 , bip.), 43.1
(CH , A, B), 54.3 (C-2, D), 64.3 (C-2, -3, a.s.), 68.7 (CH OH), 107.3 (C-5,
C 6
d (150 MHz, DEPT, DMSO-d , 298 K) 24.4 (Me), 34.9 (C-6, -10,
0
0
0
0
3
2
0
2
2
use of CHCl
3
/EtOH 3:1 as eluent, 0.336 g (0.077 mmol) compound
a.s.), 164.6 (C-2, T-0), 165.0, 165.2, 166.0 (T-0, -1, -2); m/z (linear
0
þ
11b was isolated (68% yield with respect to 4,4 -bipiperidine).
MALDIþ, matrix 2,6-dihydroxybenzoic acid) 4109.579 (MH ) (2100),
4022.492 (300), 2100.322 (200), 1989.276 (7800 a.u.).
0
5
.1.9.1. 1,1 -{4,6-Bis{4-{4,6-bis{4-{6-{[1,3-dihydroxy-2-(methyl)
0
prop-2-yl]amino}-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-s-triazin-
5.1.9.4. 1,1 -{4,6-Bis{4-{4,6-bis{4-{4,6-bis[1-hydroxy-2-(methyl)
2
4
-yl}-piperazin-1-yl}-s-triazin-2-yl}-piperazin-1yl}-s-triazine-2-yl}-
prop-2-yl-amino]-s-triazin-2-yl}-piperazin-1-yl}-s-triazin-2-yl}-pi-
perazin-1-yl}-s-triazin2-yl}-4,4 -bipiperidine (11e). Yield 62% (col-
0
0
,4 -bipiperidine (11a). Yield 46% (column chromatography: CHCl
3
/
EtOH/Et
2
O 3:1:0.7 to elute precursor 10a then CHCl
3
/EtOH 3:1 to
umn chromatography, eluent CHCl
265e275 C (dec). Found: C53.71; H: 7.31; N: 32.19%.
3
/EtOH 3.5:1), white powder, mp
ꢀ
ꢀ
elute 11a) white powder, mp 261e262 C. Found: C, 53.45; H, 7.09;
N, 27.69%. C188H
290
N
84
O32 (4236.36) requires C, 53.27; H, 6.90; N,
C
164
H
274
N
84
O
16 (3676.32) requires: C, 53.55; H, 7.51; N, 31.98%; R
f
2
7.76%; R (75% CHCl
f
3
/EtOH) 0.75; max (KBr) 3250, 2920, 2852,
n
(83% CHCl
3
/EtOH) 0.23; max (KBr) 3400, 2964, 2931, 2858, 1545,
n

8966
F. Popa et al. / Tetrahedron 68 (2012) 8945e8967
1
480, 1436, 1357, 1260, 1176, 997, 807, 737 cmꢁ1;
d
H
(500 MHz,
dendrimer adsorbed films were visualised from large scan area of
0
DMSO-d
6
, 363 K) 1.27e1.46 (106H, m: 96H, Me; 10H, H-3, -3 , -4,
20
0.2
m
m
mꢂ20
m
m
to relatively small areas of
1
m
mꢂ1
mm and
0
0
-
4 , -5, -5 , bip.), 3.47 (32H, s, CH
2
OH), 3.71e3.72 (40H, m: 32H, B;
mꢂ0.2
mm. AFM observations were repeated on different areas
0
0
8
H, H-2, -2 , -6, -6 , bip.), 3.76 (64H, s, A), 4.70 (16H, br d, J 8.0 Hz,
(100 MHz, DEPT and QC as 5 mM in
of the same film. The images were obtained from at least five
macroscopically separated areas on each sample. All images were
processed using the standard procedures for AFM. AFM images
(512ꢂ512 pixels) consist of multiple scans on x direction displaced
laterally from each other in y direction. All AFM experiments were
OH), 5.48 (16H, s, NH) ppm; d
C
DMSO-d
6
, 298 K) 24.4 (32C, Me), 43.1 (52C: 32C, A; 16C, B; 4C, C-2,
0
0
-
2 , -6, -6 , bip.), 54.2 (16C, C-2, D), 69.0 (16C, CH
2
OH), 164.6 (12C:
8
C, C-2, T-0; 4C, T-1), 165.2 (18C: 16C, C-4, -6, T-0; 2C, T-2), 165.6
ꢀ
(
2
2
12C: 8C, C-4, -6, T-1; 4C, C-4, -6, T-2); m/z (linear MALDIþ matrix
carried out under ambient laboratory conditions (about 20 C) as
previously reported. The AFM images on samples prepared in
þ
28
,5-dihydroxybenzoic acid) 3677.38 (MH ) (0.05), 3595.304 (0.18),
4
034.284 (0.20), 1951.283 (0.80), 1800.181 (4.5), 1728.1 (1.3ꢂ10 ).
both drying procedures show no observable drying patterns under
the experimental working conditions. This study is done under
comparable surface packing density, at the same adsorption time
5
.2. AFM analysis
(1 h at room temperature), at the saturation of surface with den-
Solutions of compounds 11e (in DMSO), 11b (in DMSO) and 11d
dritic molecules.
(
3
in CHCl /EtOH 3:1) were chosen to make dendrimer self assem-
blies on mica solid support.
Acknowledgements
5
.2.1. Sample preparation. Self-assembled dendrimer films were
The financial support from Grant provided by the Research
Council Romania (Project PN-II-ID-PCE-3-0128) is gratefully ac-
knowledged. The financial support from Grant provided by the
Research Council Romania (Project BD 1482) is gratefully acknowl-
edged by F.P. O.M. thanks for ‘Investing in people!’ Ph.D. scholarship,
Project co-financed by the SECTORAL OPERATIONAL PROGRAM FOR
HUMAN RESOURCES DEVELOPMENT 2007e2013 Priority Axis 1.
prepared by adsorption of each dendrimer from its bulk organic
solution at three different concentrations (about 0.01 mM, 0.1 mM
or 1 mM) on mica substrate situated in vertical position in each
dendrimer solution. Alternatively, mica surface was also placed in
the dendrimer solution oriented horizontally facing down in order
to prevent the deposition of dendrimer aggregates (or nano parti-
cles) through sedimentation. Mica plates were maintained for
various adsorption times (from 30 s to 60 min) at room tempera-
ture, by using a known protocol. Thus, the adsorbed amount of
dendrimer was monitored through the variation of the adsorption
duration and of the dendrimer concentration in organic solutions.
Prior to each adsorption experiment, the mica substrate was diced
into 1 cmꢂ1 cm plates and freshly cleaved before dendrimer ad-
sorption. After the adsorption time, each sample was withdrawn
and gently rinsed with suitable solvent to take out the excess of
dendrimers, weakly adsorbed on the self-assembled films. Then,
the dendrimer films were dried at room temperature, under
a beaker and prepared for AFM investigation. As an alternative,
some samples were dried under a weak but stable nitrogen stream
and then immediately subjected to AFM imaging. In the last situ-
‘Education and training in support for growth and development of
a knowledge based society’ Key area of intervention 1.5: Doctoral
and post-doctoral programs in support of research. Contract no.:
POSDRU/88/1.5/S/60185d‘INNOVATIVE DOCTORAL STUDIES IN A
KNOWLEDGE BASED SOCIETY’ Babe s¸ -Bolyai University, Cluj-
Napoca, Romania’. The computational centre of the University of
Reims Champagne-Ardenne (ROMEO, http://www.romeo2.fr) is
acknowledged for the CPU time donated.
2
8
Supplementary data
s
SD 1. Calculation of the rotational barrier
D
G
of compound 2a;
SD 2. Assignment of anti versus syn rotameric occurrence in the case
of compound 4b according to the ‘dipole rule’ (Fig. I); SD 3. Rota-
2
9
ation, the drying took less than 0.5 min. As recently mentioned,
1
tional dynamic behaviour of compound 4b on 400 MHz H NMR
such a short drying process does not provoke the surface aggre-
gation of biomolecules. Afterwards, all dried samples were used for
AFM examination. The AFM images on samples prepared in both
drying procedures show no observable drying patterns under the
experimental working conditions. An analysis of AFM images
shows that the dendrimer adsorption reaches a steady state satu-
s
timescale (Fig. II); SD 4. Calculation of the rotational barrier DG of
compounds 4aed (Table I); SD 5. Rotational dynamic behaviour of
compound 4e (Fig. III); SD 6. NMR spectra of compound 6a
(Fig. IVaec); SD 7. Table II, VT NMR behaviour of melamines 5a, 5b,
7
a, 7b, 7e about the bonds C(s-triazine)eN(exocyclic) in DMSO-d ;
6
SD 8. Mass spectra of compounds 11aee (Fig. VIaee); SD 9. 2D DOSY
ꢀ
ration of mica surface in about 1 h at 20 C for each used dendrimer
1
H NMR charts of compounds 10a,11b,10c,11c,10e,11e (Fig. VIIaef);
at 1 mM bulk concentration. This finding indicates that 1 mM
concentration can be considered an optimal bulk concentration to
produce in about 1 h a rather compact adsorbed film of each den-
drimer on mica. Consequently, the dendrimer films obtained
through adsorption of 1 h from 1 mM dendrimer solution were
apparently at the saturation of mica surface with dendrimers.
SD 10. Comparative VT NMR behaviour of G-1 chlorodendron 8b
versus G-1 dendritic melamine 9b (Fig. Va and b); SD 11. Table III:
1
selected (VT) H NMR data of compounds 8e11 for their behaviour
about the peripheral NH and OH groups in DMSO-d
6
; SD 12. Pe-
ripheral rotamerism in Ethylserinol B derivatives 4b, 6b, 8e10b on
13
C NMR timescale (Fig. VIII); SD 13. Integration of C-s-triazines
signals in G-2 chlorodendrons 10aee (Fig. IX); SD 14. Relevant NMR
spectra of compounds 11a, 11b, 11d and 11e (Fig. Xaed). Supple-
mentary data associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2012.07.096.
5
.3. AFM measurements
All samples were investigated by AFM operating in tapping
mode, to minimize the force exerted from the scanning tip of AFM
cantilever on the adsorbed dendrimer layers. The AFM imaging was
performed on a JEOL 4210 instrument. All measurements were
performed in air at room temperature for high lateral image reso-
lution. Standard cantilevers, non-contact conical shaped of silicon
nitride coated with aluminium, were used. The sharpened tips
were on cantilevers with a resonant frequency in the range of
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Dd
C
¼0.3 ppm (C-
a
vs -
a
”) we have Dn¼0.3ꢂ100¼30 Hz. The rate constant of
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ꢁ1
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1
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N(azaspirane) bond at 298 K should be
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¼ 1=kI > 0:033 sfor the two broad
298
lines be observed on 100 MHz time scale.
5
2
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3
2
2
5. Kessler, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 512e523 for [DdNH
/
DT]ꢂ10 , we
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1
2. For example, for the preparation of certain (un)symmetrically N-substituted
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1
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1
1
chloride with the use of 2-amino-2-methylpropanol, the resulting chlor-
odiamino-s-triazine being claimed as rubber-to-metal adhesion promoter. See
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