2,4,9-Triazaadamantanes with “Clickable” Groups: Synthesis, Structure and Applications as Tripodal Platforms

Article abstract of DOI:10.1002/ejoc.202000832

2,4,9-Triazaadamantanes (TRIADs) are promising yet scarcely available, conformationally rigid platforms for potential applications in the design of functional molecules and materials. Here, we report a facile synthesis of various N- and C7-substituted 2,4,9-triazaadamantanes, starting from amines and 4-allylhepta-1,6-dienes. A focus was placed on the synthesis of 2,4,9-triazaadamantanes bearing reactive groups (NH₂, propargyl, OH) on the bridge nitrogen atoms, which were then used to decorate the 3D scaffold by hydrazone, triazole, and boronate linkages. A reversible opening of the adamantane cage to the acyclic tris-oxime form was observed for 2,4,9-triazaadamantanes possessing hydroxy-groups on the nitrogen atoms (TRIAD-triols). This process could be controlled by temperature or by complexation of TRIAD-triol with a boronic acid. The structure of 2,4,9-triazaadamantanes and the stereodynamics at the bridge nitrogen atoms were studied by X-ray analysis and DFT calculations.

Full text of DOI:10.1002/ejoc.202000832

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: 2,4,9-Triazaadamantanes with “Clickable” Groups: Synthesis,
Structure and Applications as Tripodal Platforms
Authors: Artem Semakin, Yulia Nelyubina, Sema Ioffe, and Alexey
Sukhorukov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000832
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01/2020

10.1002/ejoc.202000832
European Journal of Organic Chemistry
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2,4,9-Triazaadamantanes with “Clickable” Groups: Synthesis,
Structure and Applications as Tripodal Platforms
Artem N. Semakin,[a],* Yulia V. Nelyubina,[b] Sema L. Ioffe,[a] Alexey Yu. Sukhorukov[a],[c],*
Dedicated to the memory of Professor William A. Smit, a distinguished scientist, lecturer, and our good friend
[a]
Dr. A. N. Semakin, Prof., Dr. S. L. Ioffe, Prof., Dr. A. Yu. Sukhorukov
Laboratory of organic and metal-organic nitrogen-oxygen systems
N. D. Zelinsky Institute of Organic Chemistry
Leninsky prospect, 47, Moscow, Russia, 119991
E-mail: sukhorukov@ioc.ac.ru, artyomsemakin@mail.ru
http://nitrogroup.tilda.ws/, https://zioc.ru/institute/laboratories/laboratory-of-organic-and-metal-organic-nitrogen-oxygen-systems-9
Prof., Dr. Yu. V. Nelyubina
Center for molecular composition studies
A. N. Nesmeyanov Institute of Organoelement Compounds
Vavilov str. 28, Moscow, Russia, 119991
[b]
[c]
Department of Innovational Materials and Technologies Chemistry
Plekhanov Russian University of Economics
Stremyanny per. 36, Moscow, Russia, 117997
Supporting information for this article is given by a link at the end of the document.
Abstract: 2,4,9-Triazaadamantanes (TRIADs) are promising yet
scarcely available, conformationally rigid platforms for potential
applications in the design of functional molecules and materials.
Here, we report a facile synthesis of various N- and C7-substituted
2,4,9-triazaadamantanes, starting from amines and 4-allylhepta-1,6-
derivatization of the six-membered ring backbone is usually not
possible, and therefore products bearing additional substituents
in the cyclohexane ring have to be prepared independently by
multistep synthetic routes.
dienes.
A
focus was placed on the synthesis of 2,4,9-
triazaadamantanes bearing reactive groups (NH2, propargyl, OH) on
the bridge nitrogen atoms, which were then used to decorate the 3D
scaffold by hydrazone, triazole and boronate linkages. A reversible
opening of the adamantane cage to the acyclic tris-oxime form was
observed for 2,4,9-triazaadamantanes possessing hydroxy-groups
on the nitrogen atoms (TRIAD-triols). This process could be
controlled by temperature or by complexation of TRIAD-triol with a
boronic acid. The structure of 2,4,9-triazaadamantanes and the
stereodynamics at the bridge nitrogen atoms were studied by X-ray
analysis and DFT calculations.
Introduction
1,3,5-Trisubstituted cyclohexane derivatives are among the most
commonly
used
synthetic
platforms
in
organic,[1]
supramolecular[2] and coordination chemistry.[3] The rigid
structure and preorganized spatial disposition of the functional
groups at the 1,3,5-axial positions of the six-membered ring
have long been recognized and applied in the design of complex
4]
molecular architectures,[2c,
supramolecular systems,[5] bio-
inspired catalysts,[1d,
capping ligands,[6a,
ion sensors,[8]
6]
7]
metallopharmaceuticals,[9]
organic
superbases[10]
and
materials.[11] The most widely applied examples of 1,3,5-
trisubstituted
cyclohexanes
include
all-cis-1,3,5-
cyclohexanetricarboxylic acid[5c, 5d, 12] and its trimethyl-substituted
analogue (Kemp’s acid[1a, 13]), all-cis-1,3,5-trihydroxycyclohexane
(cis-phloroglucitol[5b, 7i-k]) and all-cis-1,3,5-triaminocyclohexane
(TACH[7a, 7g, 7l, 11a]), as shown in Figure 1. Among the advantages
of these platforms are a high stability and the ability to modify
functional groups at the periphery. However, the direct
Figure 1. 1,3,5-Trisubstituted cyclohexane-based synthetic platforms
In this regard, 1,3,5-triazacyclohexane (hexahydro-1,3,5-triazine,
HHT) can be viewed as a more versatile and easily accessible
tripodal scaffold (Scheme 1, chart a).[14] HHT derivatives can be
1
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10.1002/ejoc.202000832
European Journal of Organic Chemistry
FULL PAPER
prepared in a single step by the cyclotrimerization of imines
generated in situ from aldehydes and amines (Scheme 1, chart
b).[15] This synthetic approach may provide access to the large
libraries of substituted HHTs, to which functional fragments can
be further attached. However, the application of 1,3,5-
triazacyclohexane derivatives as synthetic platforms is limited
due to the reversible character of imine cyclotrimerization and
the lability of the aminal moiety.[15b, 16]
biodegradable polymers,[22] polymer-bound organocatalysts,[22]
scavengers
for
boronic
acids,[22]
water-soluble
phthalocyanines,[23] capped metal complexes,[24] and dynamic
combinatorial libraries.[22] Surprisingly, 2,4,9-triazaadamantane
(TRIAD), which is a simpler analogue of TAAD, has received
much less attention and was not considered for applications as a
molecular platform (Scheme 1, chart c). Unsubstituted 2,4,9-
triazaadamantane is unknown,[18b] and to date only six of its
derivatives have been reported in the scientific and patent
literature.[25] In this work, we attempted to develop a convenient
method for the synthesis of 2,4,9-triazaadamantanes bearing
“clickable“ groups on nitrogen atoms as potential platforms for
the construction of functional molecules. We also performed
preliminarily studies on the structure, stability, and
transformations of this novel class of heterocage compounds.
Results and Discussion
Synthesis of TRIADs
Selective synthesis of 2,4,9-triazaadamantanes is challenging
and only two reports have dealt with this problem. The first
2,4,9-triazaadamantane derivative (TRIAD 2a) was obtained by
Quast and Berneth[25a] in 1983 by treatment of tris-ketone 1a
with ca. 60 equiv. of hydrazine (Scheme 2, chart a). The
required tris-ketone 1a was generated by the addition of
LiCu(CH3)2 to the corresponding tris-chloroanhydride. Due to an
irreversible intramolecular cyclization of the tris-ketone and the
intermediate mono- and bis-hydrazones, the yield of the desired
triazaadamantane 2a was only 26%. Recently, Luo and co-
workers[25b] reported the synthesis of tris-benzyl TRIAD 2b via
trial 1b. The later was generated by Stetter’s method,[26] which
involves ozonolysis of triallylcarbinol 3b followed by
hydrogenolysis of ozonide over Pd/BaSO4 at rt (Scheme 2, chart
b). Remarkably, the cyclization of tris-aldehyde 1b was relatively
slow at rt, which allowed for
a
conversion into the
triazaadamantane 2b by treatment with benzylamine in 42%
yield. The resulting N,N,N-tris-benzyl-2,4,9-triazaadamantane 2b
was used to prepare the corresponding N-nitro- and N-acyl
derivatives. However, no attempts to use primary amines other
than benzylamine and tris-carbonyl compounds other than trial
1b were performed in this study. Therefore, it was not evident
whether this method could be used to prepare other TRIAD
derivatives, especially those containing clickable groups.
From these studies it can be concluded that the intramolecular
cyclization of tris-carbonyl compounds 1 and transient mono-
and bis-imines are major side-processes, which substantially
decrease the yield of triazaadamantanes 2. We assumed that
this issue might be solved by performing the reaction of tris-
carbonyl compounds with amines at low temperatures. To
validate this, we performed a series of experiments on the
interaction of tris-carbonyl compounds 1 with N-nucleophiles
(Scheme 3, Table 1).
Scheme 1. 1,3,5-Trisubstituted cyclohexane-based synthetic platforms
The stability of a 1,3,5-triazacyclohexane unit can be greatly
increased by its incorporation into
a
cage structure, as
17]
demonstrated by several experimental[1h,
and theoretical
studies.[17d,
For
this
reason,
azaadamantanes,[19]
18]
triazaazawurtzitanes,[1h] and triaza[3]peristylanes[20] containing
nitrogen atoms in bridge positions are considered to be
promising molecular platforms for various applications (Scheme
1, chart c). Moreover, the reversible cleavage of a 1,3,5-
triazacyclohexane ring in these heterocage systems does not
lead to a loss of covalent integrity between the functional units,
thus providing a way to control the topology of the scaffold.
Recently, our group introduced 1,4,6,10-tetraazaadamantane
The required tris-carbonyls 1b-e were generated in situ by
ozonolysis of the corresponding trienes  triallylcarbinol 3b,
trimethallylcarbinol
3c,
triallylphenylmethane
3d
and
(TAAD) as
a readily available, stable and easy-to-modify
triallylcarbinol benzyl ether 3e.
multifunctional platform (Scheme 1, chart c).[17c, 19c, 21] Our group
and others have shown the application of TAAD derivatives in
the design of fluorophore-labelled natural molecules,[22]
2
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10.1002/ejoc.202000832
European Journal of Organic Chemistry
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Scheme 2. Previously reported syntheses of 2,4,9-triazaadamantanes
Unlike the procedures of Stetter[26] and Luo,[25b] in which ozonide
was cleaved by catalytic hydrogenation at room temperature, we
used reduction with Me2S to generate tris-carbonyl compounds
1b-e at -78 °C. Furthermore, N-nucleophile was added together
with the Me2S to ensure a maximum conversion of the tris-
carbonyl compound into the corresponding tris-imine (Scheme
3). These modifications resulted in much better yields of
triazaadamantanes 2 compared to the previous procedures by
Quast[25a] and Luo[25b] (vide infra). In all cases, an excess of the
N-nucleophile was needed, as it also reacted with formaldehyde,
which was formed as a by-product from the alkene ozonolysis.[27]
Table 1 summarizes some illustrative results obtained with each
N-nucleophile. As seen from these data, the desired
triazaadamantane derivatives 2 were isolated in moderate to
high yields with hydrazine, acethydrazide, tert-butyl carbazate,
benzyl carbazate and propargylamine (entries 1, 3-6). In the
case of hydrazine, 50 equiv. were required to achieve an
cyclization of tris-oxime 4h to the desired N,N,N-
trihydroxytriazaadamantane 2h, which was isolated by
crystallization from the reaction mixture in a 66% yield (entry 8,
Table 1). Due to its low solubility, product 2h was characterized
in the form of hydrochloride salt (2hHCl).
Given our interest in N,N,N-trihydroxy-derivatives of type 2h as
potential partners for boronate-triol coupling,[22] we attempted to
prepare
trimethallylcarbinol
these
products
3c,
by
ozonolysis/oximation
3d
of
and
triallylphenylmethane
triallylcarbinol benzyl ether 3e. Similar to 3b, mixtures of tris-
oximes 4 and triazaadamantanes 2 were obtained after 18 h in
these experiments (e.g., entry 9, Table 1).[29] In the case of
triallylcarbinol benzyl ether 3e, prolongation of the reaction time
to 72 h resulted in the conversion of tris-oxime 4k to the
corresponding adamantane 2k (entry 12 in Table 1).
Remarkably, benzoyl ester 2l, as a result of the oxidation of
benzyl ether moiety, was formed as a side-product (11%) in this
experiment.
acceptable
yield
of
the
corresponding
N,N,N-
triaminotriazaadamantane 2c (entry 1, Table 1). A reduction in
the amount of hydrazine to 20 equiv. resulted in a drop of the
yield to 17% (entry 2, Table 1). To our delight, reactions with
acethydrazide and carbazates afforded corresponding
triazaadamantanes 2d-f in high yields, even with a nearly
stoichiometric amount of the nucleophile (by taking into account
the presence of 3 equiv. of formaldehyde in the reaction mixture,
entries 4-6, Table 1).[28]
Importantly, tris-oximes 4 could be cyclized to corresponding
adamantanes 2 upon the action of protic acids. Complete
conversion of tris-oxime 4h to adamantane 2h was observed in
the presence of 3 equiv. of AcOH in methanol after 3 h (rt). A
reaction with
1
equiv. of HCl quantitatively gave the
corresponding hydrochloride salt 2hHCl within a few minutes.
Thus, an optimal procedure for the synthesis of N,N,N-
trishydroxytriazaadamantanes 2i,j consisted in the treatment of
the crude mixtures of 2 and 4 with acetic acid and subsequent
crystallization of the product (entries 10, 11 in Table 1).
Remarkably, the reaction with hydroxylamine gave the non-
cyclized tris-oxime 4h as the major product after 18 h (entry 7,
Table 1). Extension of the reaction time to 5 days resulted in the
Scheme 3. Optimized scheme for the synthesis of 2,4,9-triazaadamantanes 2 from trienes 3
3
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10.1002/ejoc.202000832
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Table 1. Synthesis of C- and N-substituted 2,4,9-triazaadamantanes 2 from triallylmethane derivatives 3.
Entry
product
triene
R
R1
R2
RNH2 equiv.[a]
time
Yield, %[b]
2
4
1
2c
2c
2d
2e
2f
3b
3b
3b
3b
3b
3b
3b
3b
3c
3c
3d
NH2
H
OH
50
20
7.5
7.5
7.5
10
10
10
10
10
10
72 h
43
n.o.
2
NH2
H
OH
72 h
17
56
77
76
44
n.o.
n.o.
n.o.
n.o.
n.o.
3
NHAc
NHBoc
NHCbz
CH2C≡CH
OH
H
OH
72 h
4
H
OH
72 h
5
H
OH
72 h
6
2g
4h
2h
2i + 4i
2i
H
OH
18 h
7
H
OH
18 h
n.d.
66
21
51
31
61
11
45
8
OH
H
OH
120 h
18 h
traces
33
9
OH
Me
Me
H
OH
10
11
OH
OH
18 h + 18 h[c]
18 h + 18 h[c]
traces
n.o.
n.o.
n.o.
2j
OH
Ph
OBn (2k)
OBz (2l)
12
2k + 2l[d]
3e
OH
H
10
72 h
[a] Per 1 equiv. of triene 3. [b] Isolated yields. [c] Crude product (mixture of 2 and 4) was treated with 3 equiv. of AcOH in MeOH for 18 h. [d] A mixture of 2k and
2l (ratio 86 : 14) was isolated as a single crystal phase (see experimental section). n.o. – not observed. n.d.  not determined.
Ozonolysis of the homologous triene 5 followed by treatment
with hydroxylamine afforded only the tris-oxime product 6, which
was stable and did not cyclize to the corresponding
homoadamantane derivative 7 (Scheme 4).
triazaadamantane scaffold, the retro-[2+2+2]-annulation process
has to be taken into account when performing chemical
modifications of these molecules. On the other hand, the
opening of the adamantane unit provides an interesting way to
change the topology of the scaffold from cage to an open chain.
Such a process, if reversible while controllable, may be useful
for applications in molecular switches.
Most of the obtained triazaadamantanes 2 were found to be
stable upon heating (reflux in methanol) and did not undergo
cage opening. However, the N,N,N-trihydroxy-triazaadamantane
2h was an exception. Upon heating to 60-80 °C in water, it was
converted to the corresponding tris-oxime 4h within a few
minutes (Scheme 5, chart a). Remarkably, the reaction proved
to be reversible and the cyclization of 4h back to the
adamantane 2h took 3 days at rt (or 3 h in the presence of
acetic acid). This result demonstrates that the open-chain and
adamantane forms have similar thermodynamic stabilities and
the position of equilibrium is controlled by the entropy factor.[17c]
This is confirmed by DFT calculations at the B3LYP/6-311G**
level of theory, which predict adamantane 2h to be more stable
than the isomeric tris-oxime 4h by only 2.9 kcal/mol (Scheme 5,
chart b). For TRIAD derivatives bearing hydrogen or methyl
group at the nitrogen atoms, the calculated energetic preference
of the adamantane structure vs. the open-chain form is much
higher (21.8 and 8.9 kcal/mol, respectively). Reduced
thermodynamic stability of the triazaadamantane moiety in
trihydroxy-derivatives (compared to other N-substituted TRIADs)
may be attributed to the lability of the N,N,N-trihydroxy-
triazaacyclohexane ring.[17c, 30] This is in line with the fact that
oximes are known to have the least tendency to form
cyclotrimers among other azomethines.[17d]
Scheme 4. Attempted synthesis of tris-homoazaadamantane 7
Stability of TRIADs
In previous reports by Quast[25a] and Luo,[25b] no studies on the
stability of 2,4,9-triazaadamantanes 2 were performed, since
very few representatives of this class were prepared. Therefore,
it was not known whether TRIADs 2 could undergo a retro-
[2+2+2]-annulation reaction to give tris-imines 4, which is
characteristic for compounds having a 1,3,5-triazacyclohexane
ring.[17c] As this may limit the thermal stability of
a
4
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10.1002/ejoc.202000832
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Scheme 5. Stability of TRIAD derivatives towards cage opening. DFT
calculations: B3LYP/6-311G** level of theory (E0 + ZPE). Values are given
relative to the most stable invertomer of TRIAD 2
Structure of TRIADs
The structure of the 2,4,9-triazaadamantane cage has not
received much attention in previous studies.[31] For applications
in molecular design, understanding the geometry of the scaffold
and the associated stereodynamics is needed. We were able to
perform X-ray diffraction analyses for the tris-propargyl-TRIAD
2g, TRIAD-triols 2k, 2l and TRIAD-triol salt 2hHCl, which
provided the structures of free and protonated 2,4,9-
triazaadamantane skeletons (Figures 2, 3). The neutral TRIAD
structures 2g, 2k and 2l have distorted triazaadamantane
skeletons, in which CC and CN bonds are within a relatively
narrow range of 1.5241.538 Å and 1.4621.490 Å, respectively
(Figure 2). These values are close to those observed in
adamantane (CC 1.54 Å[32]) and 1,3,5-triazaadamantane (CN
1.4681.478 Å[33]). Remarkably, in structures 2g, 2k and 2l, the
nitrogen atom N(2) with an equatorial substituent is more
deviated from the mean plane formed by bridgehead atoms C(1),
C(3) and C(5) (deviation ca. 0.58 Å) compared to the N(4) and
N(9) atoms bearing axial groups (deviations ca. 0.40.42 Å).
Propargyl groups at the N(4) and N(9) atoms in 2g are not
ideally axial, most likely due to a steric repulsion (diaxial torsion
angles are 162.2 and 165.5). In TRIAD-triols 2k and 2l, these
angles lie in the range 171.9177.6, and the nitrogen atoms are
more pyramidal. Generally, despite having different substitutions
at N- and O-atoms, the geometrical parameters of the
triazaadamantane skeleton in structures 2g, 2k and 2l are very
similar.
Figure 2. X-ray data for TRIADs 2g and 2k. Structural parameters of benzoyl
ester 2l (not shown) are very similar to benzyl ether 2k.
The cationic 2,4,9-triazaadamantanium skeleton in salt 2hHCl
(Figure 3) has a nearly Cs symmetrical structure with the length
of the CC bonds (1.523(2)1.533(2) Å) close to those observed
in the neutral 2,4,9-triazaadamantane cage in 2g,k,l (cf. with
data in Figure 2). The range of the CN bonds length is
expectedly wider (1.441(3)1.528(3) Å) due to the presence of a
tetravalent nitrogen atom N(2). Notably, the C(1)N(4) and
C(3)N(9) bonds are shortened (1.441(2)1.446(2) Å) compared
to the C(5)N(4) and C(5)N(9) bonds (1.466(2)1.470(2) Å).
This may be attributed to the strong anomeric interactions
between the equatorial lone electron pair of N(4) and N(9) and
the antibonding orbitals of the CN(2)+ bonds. Similar to 2g, 2k
and 2l, the N(2) nitrogen atom shows the highest deviation from
the mean plane formed by bridgehead atoms C(1), C(3) and
C(5). The crystal structure of 2hHCl displays a complex
network of hydrogen bonds between the HO/NH-groups of
individual 2,4,9-triazaadamantanium cations and chloride anions.
The formation of a 3D-framework is completed by weak H…H
interactions between the bridge CH2-groups of neighbouring
adamantane units (distance c.a. 2.5 Å).[34]
5
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TRIAD as a synthetic platform, it is important for the symmetrical
isomers (ideally, the all-axial isomer) to be thermodynamically
achievable. To reveal the relative stability of the invertomers,
DFT calculations were performed. As seen from data given in
Table 2, the all-axial isomer is predicted to be the most stable for
TRIADs bearing hydrogen or NH2-group on nitrogen atoms (R =
H, NH2), yet the isomer having one equatorial hydrogen nearly
has the same energy. For TRIADs with R = OH or Me, the
relative stability changes, and the ax,eq,eq-isomer becomes
more stable that is in agreement with the X-ray data for 2g, 2k
and 2l. Nevertheless, for all calculated TRIAD derivatives, the
all-axial invertomer is expected to be present in substantial
amounts, and thus can be involved in chemical reactions (vide
infra). In contrast, in all cases the all-equatorial isomer is the
least stable among four invertomers due to a repulsion between
the three lone electron pairs in the 1,3-diaxial positions (for
accumulation of the electron density see the molecular
electrostatic potential surfaces in Scheme 6).
Table 2. Calculated relative stability of invertomers
R
Relative energy of invertomer, kcal/mol[a]
E,
kcal/mol[b]
ax,ax,ax
ax,ax,eq
ax,eq,eq
3.8
eq,eq,eq
10.0
H
0
0.3
0
4.8
13.1
8.6
Figure 3. X-ray data for hydrochloride 2hHCl
OH
NH2
Me
1.6
0
1.1
8.2
0.4
0
3.0
12.3
An interesting feature of all 2,4,9-triazaadamantanes, 2g, 2k, 2l
and 2hHCl, is the ax,ax,eq-disposition of substituents at the
nitrogen atoms in the crystal phase. In the solution, different
isomeric forms may exist, which easily interconvert through the
fast inversion of the nitrogen atoms (Scheme 6, Table 2).[35] As
an indication of this, the broadening of signals is observed in the
NMR spectra of N,N,N-trihydroxy-2,4,9-triazaadamantanes 2h-l
due to dynamic exchange processes. For the application of
3.0
1.2
8.0
5.0
[a] Calculated at B3LYP/6-311G** level of theory (E0 + ZPE). Values are given
relative to the most stable isomer. [b] Conversion of eq,ax,ax invertomer to
ax,ax,ax invertomer.
Scheme 6. Inversion of nitrogen atoms in TRIAD derivatives and molecular electrostatic potential (MESP) surfaces for R = H (view on the triazine ring, B3LYP/6-
311G**)
6
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Modification of TRIADs using click-reactions
Having prepared a series of 2,4,9-triazaadamantanes 2 bearing
reactive groups at the nitrogen atoms, we studied the synthetic
potential of these products, in particular the possibility of using
them in click-like reactions (Scheme 7). Thus, adamantane 2g
possessing three propargyl groups enters the Cu-catalysed
azide-alkyne coupling (CuAAC) reaction with ethyl 5-
azidovalerate, giving the corresponding tris-adduct in 63% yield.
This product is structurally related to tris(triazolylmethyl)amines
(such as TEOTA[36]), which are efficient tripodal ligands in Cu-
catalysed reactions.
Scheme 8. Modification of TRIADs using hydrazone ligation
Recently, condensation of boronic acids with triols (boronate-triol
coupling) was introduced as perspective and efficient
a
technique for reversible click-chemistry (the formation of
degradable polymers, dynamic combinatorial libraries, etc.).[22, 37]
We have shown that tri-hydroxy-substituted TRIAD 2h reacts
smoothly with phenylboronic acid to form the corresponding
boronate adduct 10 with a betaine structure (Scheme 9).
Diamantane 10 is very stable and undergoes decomposition at
ca. 200 C. Facile formation of the diamantane skeleton
demonstrates that substituents at the nitrogen atoms in 2,4,9-
triazaadamantane can occupy all axial positions, as predicted by
the DFT calculations (see Table 2).
Scheme 7. Modification of TRIADs using CuAAC reaction
Apart from the CuAAC process, the formation of hydrazones
from aldehydes (hydrazone ligation) is a well-established click-
like reaction, which is widely used as a synthetic tool in
conjugation
chemistry.
Tris-amino-substituted
2,4,9-
triazaadamantane 2c reacts smoothly with aromatic and
aliphatic aldehydes to give stable tris-hydrazones 9a,b in high
yields (Scheme 8). These tris-hydrazone adducts can be viewed
as interesting tripodal capping ligands for transition metals.
The initial 2,4,9-triazaadamantane 2c can be prepared from
hydrazine, as shown in Table 1. However, a more efficient
procedure was found to be deprotection of the corresponding
Cbz-derivative 2f by mild hydrogenolysis over Pd/C (70% for two
steps from triene 3b). This experiment also demonstrates that
the aminal units in the triazaadamantane cage and the NN
bonds are resistant towards catalytic hydrogenation.
Scheme 9. Modification of TRIADs using boronate-triol coupling
Notably, diamantane 10 could also be prepared by the reaction
of phenylboronic acid with tris-oxime 4h. Thus, the equilibrium
between open-chain 4h and cage 2h forms can be irreversibly
shifted to the later by complexation with boronic acids.
The aforementioned examples illustrate that TRIAD derivatives 2
can be easily modified at the nitrogen atoms using different click
strategies without any problems associated with the opening of
the triazaadamantane cage.
7
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10.1002/ejoc.202000832
European Journal of Organic Chemistry
FULL PAPER
Synthesis of triallylcarbinol 3b and trimethallylcarbinol 3c.
Magnesium turnings (12 g, 500 mmol) and dry Et2O (100 ml) were placed
in a 2-neck round bottom flask equipped with a high-efficient Dimroth
condenser with an argon inlet. The dropping funnel was charged with a
mixture of diethylcarbonate (11.8 g, 100 mmol), corresponding
haloalkene (350 mmol, 30 ml of allyl bromide and 35 ml for methallyl
chloride) and Et2O (70 ml). A small amount of haloalkene (0.5-1 ml) was
added to the magnesium and the reaction was initiated by gentle heating.
Then, the heating was stopped and the mixture from the dropping funnel
was slowly added with the rate to maintain vigorous refluxing. After
completion of the addition, the reaction mixture was refluxed for 3 h, kept
overnight at rt, and the supernatant was poured into a large beaker with
ice-cold water (300 ml) and hexane (100 ml). The solid residue, which
remained in the flask, was washed with 50 ml of Et2O. Citric acid was
added to the organic-aqueous mixture until the dissolution of the
precipitate; the organic phase was separated in a funnel, washed with
brine, dried with anhydrous sodium sulphate and concentrated in vacuo.
The oily residue was subjected to vacuum distillation in a Hickman
Conclusion
In conclusion, we developed an optimized method for the
synthesis of 2,4,9-triazaadamantanes, which were scarcely
known in previous literature. Modifying the procedures
previously reported by Quast and Luo allowed us to prepare a
series of substituted 2,4,9-triazaadamantanes from various
amines (propargylamine, hydrazine, acethydrazide, carbazates
and hydroxylamine) and 4-allylhepta-1,6-dienes in moderate to
high yields. The structure of 2,4,9-triazaadamantanes and the
stereochemistry at the bridge nitrogen atoms were studied by X-
ray analysis and DFT calculations. A reversible but controllable
opening of the 2,4,9-triazaadamantane cage to open-chain tris-
imines was observed for the N,N,N-trihydroxy-substituted
derivatives for the first time. This process results in a substantial
change in the scaffold geometry, and thus can be considered for
applications in molecular switches. Modification of the bridge N-
positions in 2,4,9-triazaadamantanes through three different
click-strategies was successfully performed, demonstrating the
versatile characteristics of this new 3D scaffold.
apparatus (~5 Torr, oil bath temperature 75-85 °C (triallylmethanol[26]
)
and 80-110 °C (trimethallylmethanol[26]). The yields were 12.3 g (81%) for
3b and 14.0 g (72%) for 3c. The NMR spectra of triallylcarbinol 3b are in
accordance with literature data.[39]
2,6‐Dimethyl‐4‐(2‐methylprop‐2‐en‐1‐yl)hepta‐1,6‐dien‐4‐ol
(trimethallylcarbinol 3c). Colourless liquid. 1H NMR (CDCl3):  = 1.89 (s,
10 H, 3 CH3 and OH), 2.24 (s, 6 H, 3 CH2), 4.76 and 4.93 (2 d, J = 2.5, 6
H, C=CH2). 13C NMR (CDCl3):  = 25.0 (3 CH3), 47.9 (3 CH2), 73.5
(COH), 114.8 (3 C=CH2), 143.1 (3 C=CH2). HRMS: calculated for
C13H22ONa [M+Na+] 217.1563; found 217.1565.
Experimental Section
All reactions were performed in oven-dried (150°C) glassware. The NMR
spectra were recorded on a Bruker AM 300 spectrometer (1H 300 MHz,
13C 75 MHz) at 297 K (if not stated otherwise), with residual solvents
peaks as an internal standard. The multiplicities are indicated by s
(singlet), d (doublet), t (triplet), dd (doublet of doublets), q (quartet), ddt
(doublet of doublets of triplets), m (multiplet), or br (broad). Coupling
constants (J) are given in Hz. The HRMS were measured on the
(4-Allylhepta-1,6-dien-4-yl)benzene
(triallylphenylmethane
3d).
Allyltrimethylsilane (1.7 g, 14.9 mmol) under an argon atmosphere was
added to a solution of 4-phenylhepta-1,6-dien-4-ol[40] (900 mg, 4.8 mmol)
in freshly distilled 1,2-dichloroethane (5 ml). The reaction mixture was
cooled to the temperature of an ice-bath and scandium triflate (50 mg,
0.1 mmol) was added. After full conversion of the starting material (TLC
control), the reaction mixture was poured into a mixture of water (25 ml)
and hexane (25 ml). The organic phase was separated, and the water
phase was washed with hexane (25 ml). Combined organic extracts were
washed with brine, dried with anhydrous sodium sulphate, and
electrospray ionization (ESI) instrument with
a time-of-flight (TOF)
detector (Bruker MicroTOF). The FTIR spectra were recorded on a FT-
801 spectrometer (SIMEX). Peaks in the FT-IR spectra data are reported
in cm−1 with the following relative intensities: s (strong), m (medium), w
(weak), br (broad), or sh (shoulder). Thermogravimetric analyses (TGA)
were recorded on a Discovery SDT 650 (TA Instrument). X-ray analysis
was performed on Bruker APEX2 DUO CCD and Bruker Quest D8
diffractometers. Elemental analyses were performed at the Analytical
Center of the N.D. Zelinsky Institute of Organic Chemistry. Melting points
concentrated in vacuo. The residue contained
a crude mixture of
triallylphenylmethane 3d and (hepta-1,3,6-trien-4-yl)benzene (1H NMR
analysis, formed by a competitive dehydration of starting alcohol). The
mixture was dissolved in Et2O (20 ml) and 1 drop of boron trifluoride
diethyl etherate was added. The resulting solution was concentrated in
vacuo. During this operation, (hepta-1,3,6-trien-4-yl)benzene underwent
spontaneous tarring. The residue was subjected to column
chromatography on silica gel (eluent  hexane) to afford 3d as a
colourless liquid (260 mg, 26%). The NMR spectra is in accordance with
the literature data.[41]
(uncorrected) were determined on
a Kofler hot-stage microscope.
Column chromatography was performed using Kieselgel 40-60 μm 60A.
Analytical thin-layer chromatography was performed on silica gel plates
with QF 254. Visualization was accomplished with UV light and staining
with iodine or a solution of ninhydrin in methanol. All reagents were
commercial grade and used as received. The diethyl ether and
dichloroethane for the reactions were distilled over CaH2 prior to the
experiments. MeOH, hexane, and ethyl acetate were distilled without
drying agents. The ozone/oxygen mixture was generated from dry
({[4-(Prop-2-en-1-yl)hepta-1,6-dien-4-yl]oxy}methyl)benzene
(O-
oxygen (dried by Drierite column) using
generator (ozone output 8-12 mmol/h).
a laboratory-made ozone
benzyl triallylmethanol 3e). Sodium hydride (1.6 g of 60% suspension
in mineral oil, 39 mmol) was washed with anhydrous THF (3x10 ml)
under an argon atmosphere, and THF (5 ml) and DMPU (5 ml) were
added. The mixture was cooled on an ice bath and triallylmethanol (2.0 g,
13.2 mmol) was added. The cooling bath was removed, and the reaction
mixture was stirred for 2 h. Then, benzyl bromide (2.6 ml, 22 mmol) was
added and the reaction mixture was refluxed for 2 h. The resulting
mixture was poured in cold water (50 ml) and hexane (30 ml). The
organic phase was separated, and the water phase was washed with
hexane (30 ml). Combined organic extracts were washed with brine,
dried with anhydrous sodium sulphate, and concentrated in vacuo. The
oily residue was subjected to vacuum distillation in a Hickman still
apparatus (~0.5 Torr, oil bath temperature 150-170 °C) to afford 2.42 g of
3e (76%). Colourless liquid. 1H (CDCl3):  = 2.46 (d, J = 7.3, 6 H, 3 CH2),
4.57 (s, 2 H, CH2Ph), 5.19 (m, 6 H, C=CH2), 5.98 (m, 3 H, 3 C=CH),
7.27-7.49 (m, 5 H, Ph). 13C NMR (DEPT135, CDCl3):  = 39.9 (3 CH2),
The DFT calculations were performed using the GAMESS Computational
Chemistry Program with a Web-Based Job Submission Interface[38] and
the Gaussian 16 Rev A.03 program. For all calculations (geometry
optimization, IR frequencies, thermochemistry, MESP) the B3LYP/6-
311G** level of theory was used. Cartesian coordinates are given in
angstroms, and absolute energies are given in Hartrees (see supporting
information). Analysis of the vibrational frequencies was performed for all
optimized structures. All structures except for transition-states were
characterized by only real vibrational frequencies, and the transition-
states had one imaginary frequency. Visualization of MESP was
performed using the Web-Based Interface of the Chem Compute website.
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000832
European Journal of Organic Chemistry
FULL PAPER
63.2 (CH2Ph), 78.3 (C-O), 118.0 (3 HC=CH2), 127.3, 127.5 and 128.4
(o,m,p-Ph), 133.9 (3 HC=CH2), 139.3 (i-Ph). HRMS: calculated for
C17H22ONa [M+Na+]: 265.1563; found 265.1565.
1-{4,9-Diacetyl-7-hydroxy-2,4,9-triazatricyclo[3.3.1.13,7]decan-2-
yl}ethan-1-one (2d). Product 2d was prepared from triallylmethanol 3b
according to the general procedure with the following additions: a
solution of AcNHNH2 (1.7 g, 23 mmol) in methanol (15 ml) was used. The
reaction mixture was kept for 3 days, and then concentrated in vacuo.
Methanol (5-10 ml) and diethyl ether (until clouding) were added to the
residue and the mixture was kept in the refrigerator for 3-4 days. The
resulting precipitate was collected by filtration, washed with diethyl ether
and dried in vacuo. Yield: 547 mg (56%). White cryst., mp = 270-276 °C
(with dec.). Thermogravimetric analysis: weight loss starts at 250 °C. 1H
NMR (D2O):  = 2.03 (s, 9 H, 3 CH3), 2.18 (d, J = 2.6, 6 H, 3 CH2), 4.16
(s, 3 H, 3 CH) (OH and NH hydrogens are not observed). 13C NMR
(D2O):  = 20.2 (3 CH3), 36.6 (3 CH2), 63.5 (COH), 75.0 (3 CH), 172.4 (3
C=O). HRMS: for C13H22N6O4Na [M+Na+] calculated 349.1595; found
349.1589.
5-(But-3-en-1-yl)nona-1,8-dien-5-ol (5). Magnesium turnings (2.4 g, 100
mmol) and dry Et2O (50 ml) were placed in a 2-neck round bottom flask
equipped with a high-efficient Dimroth condenser with an argon inlet. 4-
Bromo-1-butene (0.5 ml) was added to the magnesium and the reaction
was initiated by gentle heating. A mixture of diethylcarbonate (2.5 g, 20.7
mmol) and 4-bromo-1-butene (10 g, 74 mmol) was slowly added
(portionwise) from a disposable syringe via rubber septum. After the
addition, the reaction mixture was refluxed for 3 h, kept overnight, and
the supernatant was poured into a large beaker with ice-cold water (100
ml) and hexane (50 ml). Citric acid was added until the dissolution of the
precipitate. The organic phase was separated, washed with brine, dried
with anhydrous sodium sulphate and concentrated in vacuo. The oily
residue was subjected to vacuum distillation in a Hickman apparatus (90-
120 °C) to afford 2.6 g of 5 (65%). Colourless liquid. 1H NMR (CDCl3):  =
1.36 (s, 1 H, COH), 1.55 and 2.09 (2 m, 12 H, 3 CH2CH2), 4.96 (dd, J1 =
10.1, J2 = 1.7, 3 H, 3 C=CHH), 5.04 (dd, J1 = 16.8, J2 = 1.7, 3 H, 3
C=CHH), 5.84 (ddt, J1 = 16.8, J2 = 10.1, J3 = 6.5, 3 H, 3 C=CH). 13C NMR
(DEPT135, CDCl3):  = 28.1 and 38.3 (3 CH2CH2), 74.3 (COH), 114.6 (3
HC=CH2), 138.9 (3 HC=CH2). HRMS: calculated for C13H22ONa [M+Na+]
217.1563; found 217.1562.
2,4,9-Tri-tert-butyl 7-hydroxy-2,4,9-triazatricyclo[3.3.1.13,7]decane-
2,4,9-tricarboxylate (2e). Product 2e was prepared from triallylmethanol
3b according to the general procedure with the following additions: a
solution of BocNHNH2 (3.0 g, 22.7 mmol) in methanol (15 ml) was used.
The reaction mixture was kept for 3 days, and then concentrated in
vacuo. Methanol (5-10 ml) and diethyl ether (until clouding) were added
to the residue and the mixture was kept in the refrigerator for 3-4 days.
The resulting precipitate was collected by filtration, washed with diethyl
ether and dried in vacuo. Yield: 1.15 g (77%). White cryst., mp = 248-
253 °C (with dec., darkening starts at 240 °C). 1H NMR (DMSO-d6):  =
1.40 (s, 27 H, 3 C(CH3)3), 1.83 (s, 6 H, 3 CH2), 3.74 (s, 3 H, 3 CH), 4.82
(s, 1 H, COH), 7.9-8.1 (s br, 3 H, 3 NNH). 13C NMR (DMSO-d6):  = 28.1
(3 C(CH3)3), 37.1 (3 CH2), 62.5 (COH), 76.8 (3 C(CH3)3), 78.8 (3 CH),
154.4 (3 C=O). FT-IR (KBr):  = 3295 (s, sh, br), 2978 (s), 2934 (m),
1742 (m), 1705 (s), 1682 (s), 1529 (m), 1476 (m), 1457 (m), 1392 (m),
1366 (m), 1327 (m), 1278 (m), 1252 (m), 1156 (s, sh), 1057 (m), 1020
(m), 930 (w), 873 (w), 821 (m), 756 (w, sh) cm-1.HRMS: calculated for
C22H40N6O7Na [M+Na+] 523.2851; found 523.2849.
General procedure for preparation of triazaadamantanes 2c-m and
tris-oximes 4h-j, 6. A solution of the corresponding triene 3 or 5 (3.0
mmol) in MeOH (15 ml) was cooled to the temperature of the dry ice-
acetone bath. The ozone was bubbled through the solution until an
intensive blue colour appeared. Then, argon was bubbled through the
solution until the blue colour disappeared. Me2S (3 ml) and amine were
successively added, and the dry ice-acetone bath was changed to an ice
bath. The reaction mixture was stirred for 1-2 h and then kept at 2-4 °C
(fridge) with occasional shaking for the time period indicated below.
Details on the amount of amine, reaction time and isolation procedures
are given below for each product. CAUTION! Operations should be
performed in a well-operated fume hood and precautions should be taken
to avoid the formation of explosive oxygen-organic vapor mixtures.
2,4,9-Tribenzyl 7-hydroxy-2,4,9-triazatricyclo[3.3.1.13,7]decane-2,4,9-
tricarboxylate (2f). Product 2f was prepared from triallylmethanol 3b
according to the general procedure with the following additions: a
solution of CbzNHNH2 (3.75 g, 22.6 mmol) in methanol (15 ml) was used.
The reaction mixture was kept for 3 days, and then concentrated in
vacuo. Methanol (5-10 ml) and diethyl ether (until clouding) were added
to the residue and the mixture was kept in the refrigerator for 3-4 days.
The resulting precipitate was collected by filtration, washed with diethyl
ether and dried in vacuo. Yield: 1.37 g (76%). White cryst., mp = 216-
220 °C (with dec.). 1H NMR (DMSO-d6):  = 1.90 (s, 6 H, 3 CH2), 3.4-3.5
and 4.91 (2 m, 1 H, COH), 3.83 (s, 3 H, 3 CH), 5.06 (s, 6 H, 3 CH2Ph),
7.2-7.4 (m, 15 H, 3 o,m,p-Ph), 8.80 (s, 3 H, 3 NNH). 13C NMR (DMSO-
d6):  = 37.7 (3 CH2), 62.5 (COH), 65.6 (3 CH2Ph), 77.2 (3 CH), 127.6,
127.8 and 128.3 (3 o,m,p-Ph), 136.9 (3 i-Ph), 155.3 (3 C=O). FT-IR
(KBr):  = 3364 (m), 3264 (s, br), 3222 (s, br), 3030 (m), 2956 (w, sh),
1737 (s), 1713 (s), 1563 (m), 1510 (s), 1453 (m), 1326 (m), 1250 (s),
1153 (m), 1134 (m), 1044 (m, sh), 1027 (m), 972 (w, sh), 824 (m), 750 (s),
700 (s), 602 (m, sh) cm-1. HRMS: calculated for C31H34N6O7Na [M+Na+]
625.2381; found 625.2372.
Tris(2,4,9-triamino-2,4,9-triazatricyclo[3.3.1.13,7]decan-7-ol) hydrate
(2c×1/3H2O). Product 2c was prepared from triallylmethanol 3b
according to the general procedure with the following additions: 7.5 ml
(150 mmol) of hydrazine hydrate was used. The reaction mixture was
kept for 3 days, then concentrated in vacuo to dryness (bath temperature
60 °C). Methanol (25 ml) was added to the residue, and the resulting
precipitate was collected by filtration, washed with methanol and dried in
vacuo. Yield 265 mg (43%). White cryst., mp = 172-176 °C (with dec.).
Thermogravimetric analysis: 3.8% weight loss before melting (water
desorption), fast decomposition upon melting. 1H NMR (D2O):  = 1.96 (d,
J = 2.9, 3 CH2), 4.06 (t, J = 2.9, 3 CH) (OH and NH2 hydrogens are not
observed). 13C NMR (DEPT135, D2O):  = 34.3 (3 CH2), 63.5 (COH),
78.5 (3 CH). FT-IR (KBr):  = 3275 (s), 3250 (s, sh), 3162 (s, br), 2957
(s), 2925 (s, sh), 1634 (s, sh), 1478 (m), 1461 (m), 1341 (m, sh), 1323 (s),
1211 (m), 1160 (m), 1131 (s, sh), 1024 (m, sh), 967 (m), 938 (w), 918 (m),
896 (m), 808 (m), 776 (m), 723 (m), 644 (m), 619 (w) cm-1. Elemental
analysis: calculated for C21H50N18O4 (2c×1/3H2O) C (40.76), H (8.15), N
(40.75); found C (40.62), H (8.60), N (41.03).
2,4,9-Tris(prop-2-yn-1-yl)-2,4,9-triazatricyclo[3.3.1.13,7]decan-7-ol
(2g). Product 2g was prepared from triallylmethanol 3b according to the
general procedure with the following additions: 1.9 ml (30 mmol) of
propargyl amine was used. The reaction mixture was kept overnight,
concentrated in vacuo, and then subjected for aqueous work-up (EtOAc-
brine), the organic phase was dried with anhydrous sodium sulphate and
Synthesis of 3c by hydrogenolysis of 3f. Palladium on activated
charcoal (10% Pd, 50 mg) under an argon atmosphere was added to a
suspension of 3f (150 mg, 0.25 mmol) in methanol (7.5 ml). The reaction
vessel was evacuated and filled with hydrogen 3 times (rubber balloon),
and hydrogenation was conducted for 1 h with vigorous stirring (magnetic
stirring bar). The reaction mixture was centrifuged, and the supernatant
was evaporated. Methanol (ca. 2 ml) was added to the residue methanol,
and the resulting precipitate was collected by filtration and dried in vacuo
to afford 47 mg (93%) of product 3c.
concentrated in vacuo. The residue was subjected to
a column
chromatography on silica gel (eluent hexane-EtOAc (3:1) → EtOAc) to
give crude adamantane 2g and 458 mg (76%) of 1,3,5-tris(prop-2-yn-1-
yl)-1,3,5-triazinane by-product (NMR spectra in accordance with the
literature data[42]). Crude adamantane 2g was additionally recrystallized
from diethyl ether and dried in vacuo. Yield: 355 mg (44%). White cryst.,
mp = 128-134 °C (with dec.). 1H NMR (DMSO-d6):  = 1.68 (s, 6 H, 3
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000832
European Journal of Organic Chemistry
FULL PAPER
CH2), 3.06 (s, 3 H, 3 C≡CH), 3.51 (d, J = 2.5, 6 H, 3 CH2C≡C), 3.99 (s, 3
H, 3 CH). 4.76 (s, 1 H, COH). 13C NMR (DEPT135, DMSO-d6):  = 37.9
and 41.0 (6 CH2), 64.1 (COH), 71.0, 74.1 and 81.5 (3 CH and 3 C≡CH).
FT-IR (KBr):  = 3289 (s), 3238 (s), 2960 (m), 2938 (m, sh), 2871 (w),
2115 (w), 1438 (m, sh), 1334 (s, sh), 1154 (s, sh), 1110 (s), 1085 (s),
1025 (m), 1000 (m), 906 (w), 789 (s, sh), 717 (s), 698 (s), 673 (s), 641 (s,
sh) cm-1. HRMS: calculated for C16H19N3ONa [M+Na+] 292.1420; found
292.1419. Crystals for the X-ray diffraction analysis were obtained by
crystallization using vapor diffusion of diethyl ether into the methanol
solution of 2g. CCDC 1987350 contains the supplementary
crystallographic information for 2g.
dissolved in methanol (5 ml) and acetic acid (0.5 ml) was added. The
solution was kept in a refrigerator (0 – 5 C) overnight and concentrated
in vacuo. The residual solid was washed with diethyl ether, rinsed with a
small amount of methanol, and dried in vacuo to give 244 mg (31%) of
triazaadamantane 2j. White cryst., mp = 209-212 °C (with dec.). 1H NMR
(DMSO-d6):  = 1.5-2.5 (s br, 6 H, 3 CH2), 4.31 (s, 3 H, 3 CH), 7.1-7.4 (2
m, 5 H, o,m,p-Ph), 8.59 (s, 3 H, 3 NOH). 13C NMR (DMSO-d6):  = 32.0
(CPh), 30-37 (br, 3 CH2), 74-78 (br, 3 CH), 124.7, 126.3 and 128.4
(o,m,p-Ph), 147.0 (i-Ph). FT-IR (KBr):  = 3380 (s, br), 3179 (s, br), 2965
(s), 2933 (s), 1600 (w), 1497 (m), 1450 (m), 1410 (s, sh), 1346 (m), 1317
(m), 1299 (w), 1264 (m), 1164 (s, sh), 1084 (s), 1047 (m), 1016 (m), 983
(m), 957 (m), 932 (m), 910 (m), 811 (m), 789 (m), 764 (s), 727 (w), 702
(s), 627 (m) cm-1. HRMS: calculated for C13H17N3O3Na [M+Na+]
286.1162; found 286.1161.
2,4,9-Triazatricyclo[3.3.1.13,7]decane-2,4,7,9-tetrol (2h). Product 2h
was prepared from triallylmethanol 3b according to the general
procedure with the following additions: 1.85 ml (30 mmol) of 50%
aqueous hydroxylamine solution was used. The reaction mixture was
kept for 5 days, the resulting white precipitate was collected by filtration,
washed with methanol and dried in vacuo. Yield 402 mg (66%). White
cryst., mp = 119-123 °C. Thermogravimetric analysis: 8% weight loss
upon melting, decomposition at 177 °C. It was observed that the product
is almost insoluble in common NMR solvents (CDCl3, D2O, DMSO-d6,
CD3OD, CD3CN). Upon heating conversion to tris-oxime 4h was
observed. 1H NMR (CDCl3):  = 1.9-2.0 (s br, 6 H, 3 CH2), 3.7-3.8 (s br, 3
H, 3 CH). FT-IR (KBr):  = 3539 (s), 3283 (s, br), 3218 (s, br), 2924 (s),
2879 (s), 1666 (m), 1468 (m), 1405 (s), 1379 (s), 1348 (s), 1310 (m),
1285 (m), 1143 (s), 1115 (s), 1039 (s), 1003 (m), 951 (m, sh), 906 (w),
865 (s, sh), 800 (w), 703 (w, sh), 625 (m, sh), 571 (w) cm-1. HRMS: for
C7H13N3O4Na [M+Na+] calculated 226.0798; found 226.0796.
7-Benzyloxy-2,4,9-triazatricyclo[3.3.1.13,7]decane-2,4,9-triol (2k) and
2,4,9-trihydroxy-2,4,9-triazatricyclo[3.3.1.13,7]decan-7-yl
benzoate
(2l). An inseparable mixture of 2k and 2l was obtained from O-benzyl
triallylmethanol 3e according to the general procedure with the following
additions: 1.85 ml (30 mmol) of 50% aqueous hydroxylamine solution
was used. The reaction mixture was kept for 3 days, concentrated in
vacuo and water (15 ml) was added. The oil was precipitated, which
solidified after some time. The precipitate was collected by filtration,
washed with water, rinsed with a small portion of methanol (2-3 ml) and
dried in vacuo to give 637 mg of a mixture of 2k (61%) and 2l (11%),
which could not be separated by crystallization. White crystals. 1H NMR
(DMSO-d6):  = 1.5-2.4 (s br, 6 H, 3 CH2), 4.31 (s, 3 H, 3 CH), 4.42 (s, 2
H, PhCH2), 7.3 (m, 5 H, o,m,p-Ph), 8.3-8.7 (s br, 3 H, 3 NOH). 13C NMR
(DMSO-d6):  = 30-36 (br, 3 CH2), 62.4 (PhCH2), 68.0 (COCH2), 78-82
(br, 3 CH), 127.2, 127.5 and 128.2 (o,m,p-Ph), 139.3 (i-Ph). Selected
signals of benzoate 2l: 1H NMR (DMSO-d6):  = 7.50, 7.60 and 7.91 (3 m,
5 H, o,m,p-Ph). 13C NMR (DMSO-d6):  = 74.9 (COBz), 128.7, 129.2,
133.3 (o,m,p-Ph), 164.6 (C=O). Crystals for X-ray analysis were obtained
by crystallization from methanol. A mixture of 2k and 2l (ratio 86 : 14)
was obtained as a single crystal phase. CCDC 1999152 contains the
supplementary crystallographic information for the single crystal mixture
2k+2l.
Hydrochloride 2hHCl. 4M solution of HCl in dioxane (0.25 ml, 1 mmol)
was added to a suspension of adamantane 2h (203 mg, 1 mmol) in
methanol (5 ml). Immediate dissolution of the precipitate was observed.
The resulting solution was concentrated, and the residual solid was
washed with diethyl ether, rinsed with a small amount of methanol, and
dried in vacuo. Yield 225 mg (94%). White cryst., mp = 147-152 °C (with
dec.). 1H NMR (D2O):  = 3.04 (s, 6 H, 3 CH2), 4.54 (s, 3 CH) (OH and
NH hydrogens are not observed). 13C NMR (DEPT135, D2O):  = 35.9 (3
CH2), 62.8 (COH), 78.0 (3 CH). Crystals for X-ray diffraction analysis
were obtained by crystallization using vapor diffusion of diethyl ether into
the reaction mixture. CCDC 1987938 contains the supplementary
crystallographic information for 2hHCl.
1,5-Bis(hydroxyimino)-3-[2-(hydroxyimino)ethyl]pentan-3-ol
(4h).
Product 4h was prepared from triallylmethanol 3b according to the
general procedure with the following additions: 1.85 ml (30 mmol) of 50%
aqueous hydroxylamine solution was used. The reaction mixture was
kept overnight, and then concentrated in vacuo. The residue was
subjected to a column chromatography on silica gel (eluent EtOAc) to
give 274 mg (45%) of tris-oxime 4h. Viscous oil. Rf = 0.35 (EtOAc).
Mixture of (E,E,E)-, (E,E,Z)-, (E,Z,Z)- and (Z,Z,Z)-isomers with E/Z
fragments ratio ~1 : 1.5. 1H NMR (D2O):  = 2.52 (E-fragments) and 2.71
(Z-fragments) (2 m, 6 H, 3 CH2), 7.03 (Z-fragments) and 7.59 (E-
fragments) (2 m, 3 H, 3 CH) (OH hydrogens are not observed). 13C NMR
(DEPT135, D2O):  = 34.4, 34.6, 37.1, 39.0, 39.2 and 39.3 (3 CH2), 72.2
and 72.7 (COH), 148.6, 148.8, 148.9, 149.7, 149.8, 149.9 (3 C=N). FT-IR
(thin layer):  = 3280 (s, br), 2901 (s), 1658 (m), 1433 (s), 1334 (m), 1137
(m), 1035 (m, sh), 941 (s, sh), 863 (m), 781 (w, sh), 684 (w, sh) cm-1.
HRMS: for C7H14N3O4 [M+H+] calculated 204.0982; found 204.0979.
1,3,5-Trimethyl-2,4,9-triazatricyclo[3.3.1.13,7]decane-2,4,7,9-tetrol (2i).
Product 2i was prepared from trimethallylcarbinol 3c according to the
general procedure with the following additions: 1.85 ml (30 mmol) of 50%
aqueous hydroxylamine solution was used. The reaction mixture was
kept overnight, then concentrated in vacuo and poured into an EtOAc
(100 ml)/water (50 ml) mixture. The organic phase was separated and
the water phase was washed with EtOAc (30 ml). Combined organic
extracts were washed with brine and concentrated in vacuo. The residue
was dissolved in methanol (5 ml) and acetic acid (0.5 ml) was added.
The solution was kept in the refrigerator (0 – 5 C) overnight and
concentrated in vacuo. The residual solid was washed with diethyl ether,
rinsed with a small amount of methanol and dried in vacuo to give 375
mg (51%) of triazaadamantane 2i. White cryst., mp = 145-148 °C. 1H
NMR (DMSO-d6, 322 K):  = 1.27 (s, 9 H, 3 CH3), 1.61 (s, 6 H, 3 CH2),
4.4-4.6 (s br, 1 H, COH), 7.3-7.5 (s br, 3 H, 3 NOH). 13C NMR (DMSO-d6,
322 K):  = 23.8 (3 CH3), 41-44 (br, 3 CH2), 63.8 (COH), 78.7 (3 C).
HRMS: calculated for C10H19N3O4Na [M+Na+] 268.1268; found 268.1266.
2,6-Bis(hydroxyimino)-4-[2-(hydroxyimino)propyl]heptan-4-ol
(4i).
Product 4i was prepared from trimethallylcarbinol 3c according to the
general procedure with the following additions: 1.85 ml (30 mmol) of 50%
aqueous hydroxylamine solution was used. The reaction mixture was
kept overnight, and then concentrated in vacuo. The residue was
subjected to a column chromatography on silica gel (eluent EtOAc) to
give 242 mg (33%) of tris-oxime 4i. Elution of the column with
EtOAcMeOH (1:1) afforded 154 mg (21%) of triazaadamantane 2i. Pale
yellow oil, Rf = 0.6 (EtOAc). Mixture of (E,E,E)- and (E,E,Z)-isomers (ratio
1.5 : 1). (E,E,E)-4i: 1H NMR (DMSO-d6):  = 1.80 (s, 9 H, 3 CH3), 2.30 (s,
6 H, 3 CH2), 4.69 (s, 1 H, OH), 10.43 (s, 3 H, 3 NOH). 13C NMR (DMSO-
d6):  = 15.7 (3 CH3), 44.8 (3 CH2), 73.8 (C), 154.3 (3 C=N). (E,E,Z)-4i:
1H NMR (DMSO-d6):  = 1.81 (s, 3 H, CH3, Z-fragment), 1.87 (s, 6 H, 2
7-Phenyl-2,4,9-triazatricyclo[3.3.1.13,7]decane-2,4,9-triol (2j). Product
2j was prepared from triallylphenylmethane 3d according to the general
procedure with the following additions: 1.85 ml (30 mmol) of 50%
aqueous hydroxylamine solution was used. The reaction mixture was
kept overnight, then concentrated in vacuo and poured into an EtOAc
(100 ml)/water (50 ml) mixture. The organic phase was separated; the
water phase was washed with EtOAc (30 ml). Combined organic extracts
were washed with brine and concentrated in vacuo. The residue was
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000832
European Journal of Organic Chemistry
FULL PAPER
CH3, E-fragments), 2.27 (s, 4 H, 2 CH2, E-fragments), 2.47 (s, 2 H, CH2,
Z-fragment), 4.76 (s, 1 H, OH), 10.41 (s, 1 H, NOH, Z-fragment), 10.45 (s,
2 H, NOH, E-fragments). 13C NMR (DMSO-d6):  = 15.6 (2 CH3, E-
fragments), 22.2 (CH3, Z-fragment), 40.8 (CH2, Z-fragment), 45.2 (2 CH2,
E-fragments), 74.2 (C), 154.1 (C=N, Z-fragment) and 154.4 (2 C=N, E-
fragments). HRMS: calculated for C10H20N3O4 [M+H+] 246.1448; found
246.1448.
concentrated in vacuo. The residue was subjected to a column
chromatography on silica gel (eluent EtOAc) to give 61 mg (74%) of tris-
imine 9b. Yellow oil. Rf = 0.4 (EtOAc). 1H NMR (DMSO-d6):  = 1.74 (s, 6
H, 3 CH2), 2.42 and 2.73 (2 m, 6 H and 6 H, 3 CH2CH2), 3.34 and 4.93 (2
s, 1 H, COH), 5.20 (s, 3 H, 3 CH), 7.02 (t, J = 5.0, 3 H, 3 HC=N), 7.1-7.3
(m, 15 H, 3 o,m,p-Ph). 13C NMR (DMSO-d6):  = 32.8 and 34.4 (3
CH2CH2), 37.5 (3 CH2), 64.5 and 64.6 (COH), 70.3 (3 CH), 125.8, 128.27
and 128.31 (3 o,m,p-Ph), 140.2 and 141.4 (3 i-Ph and 3 C=N). FT-IR
(KBr):  = 3166 (s, br), 2962 (s), 2676 (s, br), 1620 (m, sh), 1530 (m),
1434 (m), 1351 (s), 1319 (m), 1230 (s, sh), 1160 (s, sh), 1087 (m, sh),
1023 (w), 981 (s), 958 (m), 927 (m), 917 (m), 888 (s), 783 (s), 745 (s),
708 (s), 673 (m), 647 (m) cm-1. HRMS: calculated for C34H40N6ONa
[M+Na+] 571.3156; found 571.3145.
1,7-Bis(hydroxyimino)-4-[3-(hydroxyimino)propyl]heptan-4-ol
(6).
Product 6 was prepared according to the general procedure from triene 5
with the following additions: 1.85 ml (30 mmol) of 50% aqueous
hydroxylamine solution was used. The reaction mixture was kept
overnight, and then concentrated in vacuo. The residue was subjected to
a column chromatography on silica gel (eluent EtOAc → EtOAc-MeOH
(3:1)). Crude tris-oxime 6 was additionally recrystallized from the diethyl
ether/methanol mixture and dried in vacuo. Yield: 617 mg (84%). White
cryst., mp = 106-112 °C. Mixture of (E,E,E)-, (E,E,Z)-, (E,Z,Z)- and
(Z,Z,Z)-isomers with E/Z fragments ratio ~1 : 1. 1H NMR (CD3OD):  =
1.65 (m, 6 H, 3 CH2CH), 2.23 and 2.40 (2 m, 6 H, 3 CH2CH2), 6.71 and
7.39 (2 t, J = 5.4 and 5.9, 3 H, 3 HC=N), 10.35 and 10.70 (2 s, ~30% of
integral intensively, 3 NOH). 13C NMR (DEPT135, CD3OD):  = 20.6 and
24.9 (3 CH2CH), 35.4 and 36.2 (3 CH2CH2), 73.9, 74.0, 74.2, 74.4 (COH),
152.25, 152.31, 152.34, 152.68, 152.74 and 152.78 (3 C=N). HRMS:
calculated for C10H19N3O4Na [M+Na+] 268.1288; found 268.1272.
4-Hydroxy-9-phenyl-1,7,11-triaza-9-
borapentacyclo[7.3.1.14,12.02,7.06,11]tetradecan-1-ium-9-uide
(10).
Phenylboronic acid (122 mg, 1 mmol) was added to a suspension of
triazaadamantane 2h (203 mg, 1 mmol) in methanol (5 ml). The starting
compound dissolved within 10 min, and the precipitation of product 10
was observed. After 3 h, the precipitate was collected by filtration and
dried in vacuo. Yield: 172 mg (60%). White cryst., mp = 272-274 °C (with
dec., darkening starts at 200 °C). 1H NMR (D2O):  = 2.17 (s, 6 H, 3 CH2),
5.03 (s, 3 H, 3 CH), 7.3-7.4 and 7.4-7.5 (2 m, 3 H and 2 H, o,m,p-Ph)
(OH and NH hydrogens are not observed). 13C NMR (DEPT135, D2O): 
= 39.8 (3 CH2), 62.9 (COH), 74.4 (3 CH), 127.6, 127.8 and 130.9 (o,m,p-
Ph) (C-B signal is not observed). HRMS: for C13H15BN3O4 [M-H+]
calculated 288.1163; found 288.1169.
Ethyl
5-(4-{[4,9-bis({[1-(5-ethoxy-5-oxopentyl)-1H-1,2,3-triazol-4-
yl]methyl})-7-hydroxy-2,4,9-triazatricyclo[3.3.1.13,7]decan-2-
yl]methyl}-1H-1,2,3-triazol-1-yl)pentanoate (8). Cu(OAc)2H2O (3 mg,
0.015 mmol) was added to a stirred solution of triazaadamantane 2g (35
mg, 0.13 mmol) and ethyl 5-azidopentanoate (132 mg, 0.77 mmol) in
methanol (3 ml). After 30 min, the reaction mixture was concentrated in
vacuo. The residue was subjected to a column chromatography on silica
gel (eluent EtOAc → EtOAc-MeOH (3:1)) to afford 64 mg (63%) of tris-
triazole 8. White amorphous solid. Rf = 0.2 (EtOAc-MeOH (3:1)). 1H NMR
(HSQC, HMBC, CDCl3):  = 1.22 (t, J = 7.1, 9 H, 3 CH3), 1.62 and 1.93 (2
m, 18 H, 3 CH2CH2CH2CH2 and 3 CH2), 2.33 (t, J = 7.2, 6 H, 3 CH2C=O),
2.5-3.0 (br s, 1 H, OH), 3.91 (s, 3 H, 3 CH), 4.10 (q, J = 7.1, 6 H, 3
CH2CH3), 4.14 (s, 6 H, 3 NCH2C), 4.32 (t, J = 7.5, 6 H, 3 CH2CH2N), 7.57
(s br, 3 H, 3 C=CH). 13C NMR (HSQC, HMBC, CDCl3):  = 14.3 (3 CH3),
21.9 and 29.7 (3 CH2CH2CH2CH2), 33.5 (3 CH2C=O), 38.7 (3 CH2), 48.4
(3 NCH2C), 50.0 (3 NCH2CH2), 60.5 (3 CH2CH3), 66.1 (COH), 72.6 (3
CH), 122.3 (3 C=CH), 146.7 (3 C=CH), 173.1 (3 C=O). HRMS: calculated
for C37H59N12O7 [M+H+] 783.4624; found 783.4619.
Acknowledgements
This work was supported by the Russian Foundation for Basic
Research (grant 20-03-00510_a). The X-ray diffraction data
were collected with the financial support from the Ministry of
Science and Higher Education of the Russian Federation using
the equipment of the Center for molecular composition studies of
INEOS RAS and the Department of Structural Studies of the
Zelinsky Institute of Organic Chemistry. For the computational
part of this work, the Extreme Science and Engineering
Discovery Environment (XSEDE) was used, which is supported
by the National Science Foundation.
2,4,9-Tris({[(4-methoxyphenyl)methylidene]amino})-2,4,9-
Keywords: adamantanes• click chemistry • cyclotrimerization •
triazatricyclo[3.3.1.13,7]decan-7-ol (9a). p-Anisaldehyde (250 l, 2.03
mmol) was added to a stirred suspension of triazaadamantane 2c (120
mg, 0.58 mmol) in methanol (2.5 ml). The starting material immediately
dissolved, and a yellow precipitate was formed within 10-15 min. After 30
min, the precipitate was collected by filtration, washed with methanol,
and dried in vacuo. Yield: 272 mg (85%). Pale yellow cryst., mp = 185-
189 °C (with dec., darkening starts at 160 °C). 1H NMR (DMSO-d6):  =
1.97 (s, 6 H, 3 CH2), 3.31 and 5.10 (2 s, 1 H, COH), 3.77 (s, 9 H, 3
OCH3), 5.68 (s, 3 H, 3 CH), 6.85 and 7.49 (2 d, J = 8.7, 12 H, 3 C6H4),
7.88 (s, 3 H, 3 HC=N). 13C NMR (DEPT135, DMSO-d6):  = 38.2 (3 CH2),
55.1 (3 OCH3), 64.45 and 64.54 (COH), 71.2 (3 CH), 113.8 (3 m-
C6H4OCH3), 127.3 (3 o-C6H4OCH3), 128.8 (3 i-C6H4OCH3), 138.0 (3
C=N), 160.3 (3 =C-O). FT-IR (KBr):  = 3419 (s, br), 2999 (w), 2956 (m),
2932 (m, sh), 2835 (w), 1608 (s), 1512 (s), 1462 (m, sh), 1350 (m, sh),
1305 (m), 1250 (s), 1168 (s), 1063 (m), 1031 (m), 1002 (m), 901 (w), 878
(w), 830 (m), 765 (m, sh), 728 (w), 611 (w) cm-1. HRMS: calculated for
C31H35N6O4 [M+H+] 555.2714; found 555.2725.
hydrazones • ozonolysis
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1 h of stirring, the reaction mixture was
11
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000832
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.202000832
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
2,4,9-Triazaadamantanes (TRIADs) are a poorly investigated class of hetrocage molecules, which have the potential for applications
as synthetic platforms. Here, comprehensive studies on the synthesis, structure and stability of TRIADs were performed. Facile
modification of bridge N-positions in TRIADs through different click-strategies demonstrates the versatile characteristics of this new
3D scaffold.
Key Topic: Adamantane chemistry
Institute and/or researcher Twitter usernames: @SukhorukovAlex
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This article is protected by copyright. All rights reserved.