Multigram four-step synthesis of 1,4,7-triazacyclononanes with 2Ra/Rb N-functionalization pattern by starting from diethylenetriamine

Article abstract of DOI:10.1002/ejoc.201402821

Polyazamacrocycles and their derivatives are appreciated for the strength of their corresponding metal complexes. 1,4,7-Triazacyclononane (TACN) derivatives have been employed in an ever increasing number of applications. To this day, all synthetic routes to TACN derivatives that have identical or differing substituents require the initial preparation of unprotected TACN. Herein, we report the four-step synthesis of TACN derivatives that have a 2R_a/R_b N-functionalization pattern by starting from diethylenetriamine and employing an organic template strategy.

Full text of DOI:10.1002/ejoc.201402821

Job/Unit: O42821
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FULL PAPER
DOI: 10.1002/ejoc.201402821
Multigram Four-Step Synthesis of 1,4,7-Triazacyclononanes with 2Ra/Rb N-
Functionalization Pattern by Starting from Diethylenetriamine
Guillaume Gros[a] and Jens Hasserodt*[a]
Keywords: Macrocycles / Chemoselectivity / Tridentate ligands / Amination / Alkylation
Polyazamacrocycles and their derivatives are appreciated for
the strength of their corresponding metal complexes. 1,4,7-
Triazacyclononane (TACN) derivatives have been employed
in an ever increasing number of applications. To this day, all
synthetic routes to TACN derivatives that have identical or
differing substituents require the initial preparation of unpro-
tected TACN. Herein, we report the four-step synthesis of
TACN derivatives that have a 2Ra/Rb N-functionalization
pattern by starting from diethylenetriamine and employing
an organic template strategy.
or HBr solution). Despite its widespread use, the Richman–
Atkins route thus continues to suffer from major draw-
backs, that is, long reaction times (7–10 d), too many steps
(6), and moderate yields (50–60%), and it is clearly not
atom-economic.
Introduction
Ligands based on the macrocycle 1,4,7-triazacyclo-
nonane (TACN) are increasingly popular among coordina-
tion chemists because of the strength of their complexes
with metal ions. A significant number of N-functionaliza-
tion patterns have therefore been developed for this sys-
tem.[1] The corresponding metal complexes have been con-
sidered for diverse applications that range from catalysis,
enzyme mimicking, and the design of magnetic resonance
imaging (MRI) contrast agents and positron emission to-
mography (PET) radiotracers.[2] Increasingly, these com-
plexes are active in a multimodal manner, and chemists thus
need to install an extra anchor point, either by a C-substitu-
tion of the macrocycle or by differentiation of the three sec-
ondary amine sites during alkylation, with one substituent
serving as the anchor point.
For the last three decades, TACN derivatives have been
prepared by exhaustive or selective alkylation of the unpro-
tected macrocycle TACN. The latter is traditionally per-
formed by the Richman–Atkins route that starts from di-
ethylenetriamine (DETA, 1),[3] and this approach has seen
only minor modifications over the years.[4] The key step
consists of the reaction between a trisulfonamide di-
sodium salt of DETA and ethylene glycol ditosylate. The
Thorpe–Ingold-like effect from the bulky tosyl groups is re-
sponsible for the high macrocyclization yields and little loss
to polymerization.[5] However the same presence of the
tosyl groups forces one to apply drastic conditions for their
subsequent removal (heating in concentrated sulfuric acid
Very recently, Denat et al. patented an elegant strategy
for the macrocyclization of DETA (1) by employing an or-
ganic template, namely, chloroacetaldehyde (2, see
Scheme 1).[6] The intermediate bicyclic ammonium salt
(compare to 6a–6g in Scheme 2) underwent ring-opening to
give the macrocycle by a reduction reaction with a complex
metal hydride. The trimethyl version of this bicyclic inter-
mediate has already been reported by Koek et al.,[7] but it
was Denat et al. who obtained it in only two steps from
the bulk chemical DETA (1) and chloroacetaldehyde (2).
Unfortunately, this route still suffers from the need to re-
move three benzyl protecting groups from the initial macro-
cycle by a catalytic hydrogenation and employ unprotected
TACN in the installation of another N-functionalization
pattern. The route significantly diminishes the time required
to prepare free TACN but maintains the need to realkylate
[a] Laboratoire de Chimie, UMR CNRS 5182, Ecole Normale
Supérieure de Lyon,
46 Allée d’Italie, 69364 Lyon, France
Scheme 1. Efficient access to TACN with a 2Ra/Rb substitution
pattern. All known syntheses of TACN ligands with an N-function-
alization pattern involve the preparation of unsubstituted TACN
and proceed through arduous, low-yielding routes.
E-mail: jens.hasserodt@ens-lyon.fr
www.ens-lyon.fr/CHIMIE
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402821.
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with the chosen pendent arms. Therefore, it is as atom- degraded rapidly, synthetic intermediates 5a–5c are stable
economic as the Richman–Atkins route and does not and can be stored under air at room temperature for weeks.
greatly improve the overall yield.
These bicyclic compounds are easily purified by precipitat-
ing the impurities in diethyl ether and removing them by
filtration. Compounds 5a–5c lend themselves surprisingly
well to the regiospecific quaternization of the bridgehead
nitrogen by using a wide range of alkylating reagents in
acetonitrile at room temperature (see Table 1).
Table 1. Synthesized compounds.
Scheme 2. Four-step approach to TACN with a 2Ra/Rb N-func-
tionalization pattern by starting from low-cost diethylenetriamine
(DCM = dichloromethane).
In view of this, a wide range of functionalization tech-
niques have been developed over the years to prepare
TACN with different pendent arms. Most of them rely on:
(a) the introduction of protecting groups, (b) pH control,
and/or (c) steric hindrance.[8] All of the techniques are selec-
tive, not specific, and thus require separation/purification
steps that, in view of the polyamine nature of the object,
lead to significant losses in yield. They are also time con-
suming and do not easily submit to scaleup. In summary,
the substitution patterns that are found in 3 (see Scheme 1)
require the prior preparation of unprotected TACN, and
the syntheses of ligands such as 3 involve between 7 and
15 steps over 2 to 4 weeks, start from 10 g of DETA (1),
and furnish between 100 mg and 1 g of final product (1 to
5% yield). Herein, we present a greatly improved synthetic
approach to TACN with a 2Ra/Rb N-functionalization
pattern. This strategy does not involve unprotected TACN
and furnishes the target in only four steps, over 3–4 d, and
in overall yields of approximately 40% (see Schemes 1 and
2).
The obtained ammonium salts can be precipitated in di-
ethyl ether as brown colored salts 6a–6g in acceptable to
excellent yields (from 29 to 78% for one step). However,
their exposure to moisture needs to be kept at a minimum
as they are quite hygroscopic. The subsequent treatment of
6a–6g with complex metal hydrides furnishes the desired
substituted macrocycles in remarkable purity and speed.
The reaction with NaBH4 was complete in less than 15 min.
The first step (see Scheme 2) consists of a conventional
reductive amination reaction, which is usually accomplished
by heating a solution of the amine and aldehyde prior to
Results and Discussion
To circumvent the shortcomings that are mentioned the addition of a complex metal hydride such as NaBH4 or
above, we chose to exploit the potential chemoselectivity LiAlH4. When applied to the installation of two benzyl or
that is offered by DETA to introduce only two terminal two p-methoxybenzyl groups, this procedure allows for the
alkyl groups. In conjunction with the strategy by Denat et convenient preparation of 4a and 4b (see Scheme 3), which
al., this would allow for the formation of TACN with a are precipitated and stored as their hydrochloride salts
substitution pattern that is found in 3. Reductive amination upon treatment with hydrochloric acid. On the other hand,
is generally regarded as the method of choice to distinguish dipicolyl derivative 4c resisted this strategy and had to be
between secondary and primary amines, and indeed, we stored in its neutral form over KOH pellets. Milder complex
found that its application to the synthesis of 1,7-dibenzyl- hydrides, such as NaCNBH3 and NaBH(OAc)3, failed to
ated or 1,7-dipicolylated DETA (i.e., 4a–4c) was efficient. give useful results. As demonstrated by MS monitoring,
The products did not require subsequent purification (see these reagents produced mixtures of mono-, di-, and trisub-
Scheme 2).[9]
stituted DETA, which are impossible to separate by prepar-
The treatment of 4a–4c with chloroacetaldehyde (2) ac- ative chromatographic methods. This lack of selectivity was
cording to the strategy of Denat et al. led to the straightfor- reported to be a result of an equilibrium between the corre-
ward formation of bicyclic octahydroimidazo[1,2-a]pyr- sponding bis(imine) and aminal (see Scheme 3),[10] the latter
azines 5a–5c. In contrast to the unsubstituted bicycle that of which was more difficult to reduce than the former.
2
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Multigram Four-Step Synthesis of 1,4,7-Triazacyclononanes
we wanted to establish a route that lends itself to significant
scaleup, we investigated the removal of the PMB group
from the compounds in Table 1 by using oxidants such as
ceric ammonium nitrate (CAN) and 2,3-dichloro-5,6-di-
cyano-1,4-benzoquinone (DDQ). However, we failed to iso-
late any target compound. Likewise, the use of trifluoro-
acetic acid led to degradation, as a significant reaction only
took place in the presence of an excess amount of trifluoro-
acetic acid (TFA) at reflux. To our great satisfaction, 2-
chloroethyl chloroformate (ACE-Cl), which was previously
reported by Ortitz et al., allowed for the smooth removal
of the PMB moiety in two steps: (a) conversion into carb-
amate 7 and (b) subsequent solvolysis in refluxing MeOH
(see Scheme 5).[12] By following these conditions, we ob-
tained 5 g of a key intermediate of our research on magne-
togenic probes,[2a] namely, 1,4-(pyridin-2-ylmethyl)-1,4,7-
triazacyclononane (DPTACN), in five steps and 16% over-
all yield by starting from low-cost diethylenetriamine.
Scheme 3. Dialkylation of DETA.
In a similar effort to that above, that is, to perform a
reductive amination in the presence of more sensitive sub-
stituents, we examined the opening of the bicycle to afford
the macrocycle by using deactivated complex hydrides. The
use of NaCNBH3, however, is precluded, as Koek and De-
nat.[6a,7] have already shown that the bicyclic ammonium
salt prefers to react with the cyanide to give a nitrile (C–
C bond formation). We therefore turned our attention to
NaBH(OAc)3 and were delighted that the pendent carb-
oxylic ester group tolerated the reaction conditions. By
using this mild reductive agent, we experienced the slower
formation of the macrocycle formation, but this change was
insignificant (1–2 h) in comparison to the rate obtained by
using sodium tetraborohydride (see Scheme 4).
Scheme 5. Access to DPTACN by mild removal of PMB (Pi =
picolyl).
Conclusions
A synthetic route of unparalleled efficiency to provide
unevenly substituted triazacyclononanes is presented. This
approach allows for the preparation of hitherto inaccessible
quantities of a class of compounds that are widely recog-
nized for their macrocyclic and polyamine character but are
difficult to access. Not a single step of chromatographic pu-
rification was necessary. The requirements of this new route
for alkylation and subsequent smooth deprotection are rec-
onciled by a combination of the use of the PMB group and
the reagent 2-chloroethyl chloroformate. This allows for the
possibility of the convenient introduction of one new pen-
dent arm and the opportunity to choose that N-functionali-
zation.
Scheme 4. Bicycle opening with a mild reductive agent.
The attractiveness of this new synthetic route is also
noted in the ease of purification. The alternation between
neutral and salt-like states permits access to the final prod-
uct without chromatography in overall yields of 21 to 44%
over four steps and in less than 4 d (see Table 1).
The choice of the para-methoxybenzyl (PMB) moiety
was primarily motivated by its role as a protecting group
and the affordability of the corresponding reagent PMB-Cl.
Although the cleavage of PMB ethers to furnish alcohols is
well documented, cases of PMB removal from amines are
rare. For an efficient cleavage, it appears that the dimeth-
oxybenzyl group (DMB) has to be employed, which re-
Experimental Section
General Procedure A – Selective Dialkylation of Diethylenetriamine
(1) by Reductive Amination: Diethylenetriamine (5.0 mL,
46.1 mmol) was added to a solution of the aldehyde (2 equiv.) in
absolute EtOH (350 mL). The mixture was heated at 50 °C for 2 h
quires the use of far more expensive DMB-Cl.[11] Because and then was cooled to room temperature. NaBH4 (8.7 g,
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369 mmol) was added, and the mixture was again heated at 50 °C
for 2 h. The solvent was removed under reduced pressure, and
NaOH (1 m solution, 250 mL) was added to the residue. The mix-
ture was extracted with DCM (3ϫ 250 mL). The combined organic
phases were washed with NaOH (1 m solution, 250 mL), dried with
Na2SO4, and filtered.
General Procedure C – Formation of the 4-Alkylated 1,7-Bis(alkyl-
ated) Octahydroimidazo[1,2-a]pyrazin-4-ium Halide: The alkylating
agent (1 equiv.) was added to a vigorously stirred mixture of 1,7-
bis(alkylated) octahydroimidazo[1,2-a]pyrazine (1 equiv.) and
K2CO3 (2 equiv.) in MeCN (5 mL/mmol). The reaction was stirred
for 18 h, and then the salt was removed by filtration through a pad
of Celite. The solvent was removed under reduced pressure, and
the residue was dissolved in a minimum amount of DCM. The
DCM solution was added dropwise to a large volume of diethyl
ether (20 mL/mmol). The resulting hygroscopic precipitate was fil-
tered through a sintered glass funnel and washed with diethyl ether.
An additional crop of product could be obtained by applying this
procedure to the residue that was obtained by concentrating the
filtrate to dryness.
1,7-Dibenzyldiethylenetriamine Tris(hydrochloride) (4a): The com-
pound was synthesized by employing benzaldehyde and following
procedure A. The DCM solution was concentrated to half its vol-
ume and then treated with concentrated HCl (12.5 mL, 37%). The
resulting precipitate was filtered through a sintered glass funnel and
then washed with DCM and diethyl ether to give 4a (17.2 g, 95%
1
yield) as a colorless powder. H NMR (300 MHz, D2O): δ = 7.44
(m, 10 H), 4.26 (s, 4 H), 3.38 (s, 8 H) ppm. MS (ESI): m/z = 284.2
[M + H]+.
4-(2-Ethoxy-2-oxoethyl)-1,7-dibenzyloctahydroimidazo[1,2-a]pyr-
azin-4-ium Bromide (6b): Employing compound 5a (308 mg,
1.0 mmol) and ethyl bromoacetate and following procedure C af-
forded compound 6b (219 mg, 46 % yield) as a yellowish oil.
HRMS (ESI): calcd. for C24H32N3O2 [M]+ 394.2489; found
394.2499.
1,7-Bis(pyridin-2-ylmethyl)diethylenetriamine (4c): The compound
was synthesized by employing 2-pyridinecarbaldehyde and follow-
ing procedure A. After the DCM solution was dried with Na2SO4
and filtered, the solvent was removed under reduced pressure to
give 4c (11.4 g, 92% yield) as a reddish oil. 1H NMR (300 MHz,
CDCl3): δ = 8.52 (d, 1 H), 8.43 (d, 1 H), 7.60 (m, 2 H), 7.49 (d, 1
H), 7.35 (d, 1 H), 7.11 (m, 2 H), 3.98 (d, 1 H), 3.71 (s, 2 H), 3.61
(d, 1 H), 3.25 (m, 1 H), 3.12 (m, 1 H), 2.99–2.87 (m, 3 H), 2.75 (d,
1 H), 2.53–2.41 (m, 4 H), 2.13 (t, 1 H) ppm. 13C NMR (76 MHz,
CDCl3): δ = 159.6, 158.3, 149.2, 148.7, 136.4 (d), 123.2, 122.7,
122.0, 121.9, 81.3, 64.3, 56.7, 52.0, 51.4, 50.4, 50.0 ppm. HRMS
(ESI): calcd. for C18H24N5 [M + H]+ 310.2026; found 310.2012.
4-(4-Methoxybenzyl)-1,7-bis(pyridin-2-ylmethyl)octahydroimidazo-
[1,2-a]pyrazin-4-ium Chloride (6g): Employing compound 5c
(6.10 g, 19.7 mmol) and 4-methoxybenzyl chloride and following
procedure C afforded compound 6g (6.89 g, 75% yield) as a yellow-
ish oil. HRMS (ESI): calcd. for C26H32N5O [M]+ 430.2601; found
430.2582.
General Procedure D – Macrocycle Opening by Using NaBH4:
NaBH4 (2 equiv.) was added in small portions to a solution of the
4-alkylated-1,7-bis(alkylated) octahydroimidazo[1,2-a]pyrazin-4-
ium halide (1 equiv.) in absolute EtOH (10 mL/mmol) at room
temp. The reaction was stirred for 10–15 min and monitored by
MS. The solvent was then removed under reduced pressure to give
a residue that was dissolved in NaOH (1 m aqueous solution,
10 mL/mmol). The resulting solution was extracted with DCM
(3ϫ10 mL/mmol), and the combined organic phases were washed
with NaOH (1 m aqueous solution, 10 mL/mmol), dried with
Na2SO4, and filtered. The solvent was removed under reduced pres-
sure to give the ring-opened product.
General Procedure B – Formation of the 1,7-Bis(alkylated) Octa-
hydroimidazo[1,2-a]pyrazine:
A solution of chloroacetaldehyde
(45% w/w in water, 1 equiv.) in MeCN (5 mL/mmol) was added
dropwise to a solution of the 1,7-bis(alkylated) diethylenetriamine
(1 equiv.) and K2CO3 (2 equiv.) in MeCN (5 mL/mmol) as the mix-
ture was vigorously stirred. The reaction was stirred for 4 h, and
then the salt was removed by filtration through a pad of Celite.
The solvent was removed under reduced pressure, and the residue
was dissolved in a minimum amount of DCM. The DCM solution
was added dropwise to a large volume of ether (20 mL/mmol). The
mixture was filtered through a sintered glass funnel, and the filtrate
was concentrated under reduced pressure to give the desired prod-
uct. The purification of the recovered solid/oily phase was repeated
if necessary.
4-(4-Methoxybenzyl)-1,7-bis(pyridin-2-ylmethyl)-1,4,7-triazacyclo-
nonane (3g): Employing compound 6g (2.54 g, 5.45 mmol) and fol-
lowing procedure D afforded compound 3g (1.78 g, 76% yield) as
a yellowish oil. 1H NMR (300 MHz, CDCl3): δ = 8.52 (d, 2 H),
7.65 (t, 2 H), 7.52 (d, 2 H), 7.25 (d, 2 H), 7.14 (t, 2 H), 6.84 (d, 2
H), 3.83 (s, 3 H), 3.80 (s, 4 H), 3.56 (s, 2 H), 2.93 (s, 4 H), 2.87 (m,
4 H), 2.78 (m, 4 H) ppm. 13C NMR (76 MHz, CDCl3): δ = 160.7,
158.4, 148.9, 136.2, 132.3, 130.1, 123.2, 121.7, 113.7, 64.7, 62.6,
55.7 (d), 55.6, 55.2 ppm. HRMS (ESI): calcd. for C26H34N5O [M
+ H]+ 432.2756; found 432.2739.
1,7-Dibenzyloctahydroimidazo[1,2-a]pyrazine (5a): Employing the
neutral form of compound 4a (822 mg, 2.90 mmol) and following
procedure B afforded compound 5a (810 mg, 91% yield) as a yel-
1
lowish oil. H NMR (300 MHz, CDCl3): δ = 7.46 (m, 10 H), 4.02
(d, 1 H), 3.71 (s, 2 H), 3.63 (d, 1 H), 3.25 (m, 1 H), 3.12 (m, 1 H),
2.99–2.87 (m, 3 H), 2.75 (d, 1 H), 2.53–2.41 (m, 4 H), 2.13 (t, 1
H) ppm. 13C NMR (76 MHz, CDCl3): δ = 163.3, 139.3, 138.1,
129.2 128.5, 128.2, 128.2, 127.0, 126.9, 81.5, 65.9, 62.9, 57.8, 56.7,
51.9, 51.2 ppm. HRMS (ESI): calcd. for C20H26N5 [M + H]+
308.2121; found 308.2108.
General Procedure E – Bicycle Opening by Using NaBH(OAc)3:
NaBH(OAc)3 (2 equiv.) was added in small portions to a solution
of the 4-alkylated 1,7-bis(alkylated) octahydroimidazo[1,2-a]pyr-
azin-4-ium halide (1 equiv.) in DCM (10 mL per mmol) at room
temp. The mixture was stirred for 1–2 h, and the progress was mon-
itored by MS. The reaction was quenched by the addition of NaOH
(1 m aqueous solution, 10 mL/mmol), and the resulting mixture was
extracted with DCM (3ϫ10 mL/mmol). The organic phases were
combined, washed with NaOH (1 m solution, 10 mL/mmol), dried
with Na2SO4, and filtered. The solvent was removed under reduced
pressure to give the ring-opened product.
1,7-Bis(pyridin-2-ylmethyl)octahydroimidazo[1,2-a]pyrazine
(5c):
Employing compound 4c (11.4 g, 40.0 mmol) and following pro-
cedure B afforded compound 5c (10.31 g, 84% yield) as a yellowish
1
oil. H NMR (300 MHz, CDCl3): δ = 8.52 (d, 1 H), 8.43 (d, 1 H),
7.60 (m, 2 H), 7.49 (d, 1 H), 7.35 (d, 1 H), 7.11 (m, 2 H), 3.98 (d,
1 H), 3.71 (s, 2 H), 3.61 (d, 1 H), 3.25 (m, 1 H), 3.12 (m, 1 H),
2.99–2.87 (m, 3 H), 2.75 (d, 1 H), 2.53–2.41 (m, 4 H), 2.13 (t, 1
H) ppm. 13C NMR (76 MHz, CDCl3): δ = 159.6, 158.3, 149.2,
148.7, 136.4 (d), 123.2, 122.7, 122.0, 121.9, 81.3, 64.3, 56.7, 52.0,
51.4, 50.4, 50.0 ppm. HRMS (ESI): calcd. for C18H24N5 [M + H]+
310.2026; found 310.2012.
4-(2-Ethoxy-2-oxoethyl)-1,7-dibenzyl-1,4,7-triazacyclononane (3b):
Employing compound 6b (220 mg, 0.46 mmol) and following pro-
4
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Multigram Four-Step Synthesis of 1,4,7-Triazacyclononanes
[3] J. E. Richman, T. J. Atkins, J. Am. Chem. Soc. 1974, 96, 2268–
2270.
[4] a) W. Raßhofer, F. Vögtle, Justus Liebigs Ann. Chem. 1977,
1340–1343; b) K. Wieghardt, W. Schmidt, B. Nuber, J. Weiss,
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[5] J. S. Bradshaw, K. E. Krakowiak, R. M. Izatt (Eds.), Aza-
Crown Macrocycles: An Overview, in: Chemistry of Heterocyclic
Compounds: Aza-Crown Macrocycles, vol. 51, John Wiley &
Sons, Hoboken, 2008.
[6] a) F. Denat, Y. Rousselin, P. Desogere, F. Boschetti, C. Bern-
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cedure E afforded compound 3b (177 mg, 97% yield) as a yellowish
oil. 1H NMR (500 MHz, CDCl3): δ = 7.45–7.20 (m, 10 H), 4.19
(q, J = 7.0 Hz, 2 H), 3.69 (s, 4 H), 3.44 (s, 2 H), 2.98 (m, 4 H),
2.91 (m, 4 H), 2.81 (s, 4 H), 1.30 (t, J = 7.0 Hz, 3 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 172.2, 139.9, 129.2, 128.2, 126.9,
62.8, 60.3, 59.2, 55.4, 55.3, 54.9, 14.4 ppm. HRMS (ESI): calcd. for
C24H34N3O2 [M + H]+ 396.2646; found 396.2666.
PMB Deprotection – 1,4-Bis(pyridin-2-ylmethyl)-1,4,7-triazacyclo-
nonane (8): 2-Chloroethyl chloroformate (0.25 mL, 2.5 mmol) was
added to a solution of 3g (1.0 g, 2.3 mmol) and K2CO3 (640 mg,
4.6 mmol) in DCM (20 mL). The mixture was stirred for 2–3 h,
and the progress of the reaction was monitored by MS. The reac-
tion mixture was filtered through pad of Celite, and the solvent
was removed under reduced pressure. The residue was dissolved in
MeOH (20 mL), and the resulting solution was heated at reflux for
15 min. The solvent was again removed under reduced pressure,
and the residue was purified by flash chromatography (basic alu-
mina, gradient from 0 to 10% MeOH in DCM) to give compound
8 (265 mg, 37% yield) as an orange oil. 1H NMR (300 MHz,
CDCl3): δ = 8.66 (d, 2 H), 7.59 (t, 2 H), 7.22 (m, 4 H), 3.93 (s, 4
H), 3.21 (m, 4 H), 3.01 (t, 4 H), 2.75 (s, 4 H) ppm. 13C NMR
(76 MHz, CDCl3): δ = 158.2, 149.6, 136.8, 122.8, 122.6, 60.9, 53.1,
49.7, 45.5 ppm.
[7] J. H. Koek, E. W. J. M. Kohlen, Tetrahedron Lett. 2006, 47,
3673–3675.
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Acknowledgments
Financial support from the French Research Ministry and from the
Centre National de la Recherche (CNRS) is gratefully acknowl-
edged.
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Received: June 26, 2014
Published Online: ᭿
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Job/Unit: O42821
/KAP1
Date: 20-11-14 13:05:28
Pages: 6
G. Gros, J. Hasserodt
FULL PAPER
Macrocycles
G. Gros, J. Hasserodt* ...................... 1–6
Multigram Four-Step Synthesis of 1,4,7-
Triazacyclononanes with 2Ra/Rb N-Func-
tionalization Pattern by Starting from Di-
ethylenetriamine
A four-step synthetic route to 1,4,7-triaza-
This allows for the atom-economic, multi-
gram syntheses of several substituted de-
rivatives with excellent overall yields in less
than five days.
cyclononanes with
a 2Ra/Rb N-func-
tionalization pattern is presented. The for-
mation of the macrocycle is greatly facili-
tated by the use of an organic template.
Keywords: Macrocycles / Chemoselectivity /
Tridentate ligands / Amination / Alkylation
6
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Eur. J. Org. Chem. 0000, 0–0