Synthesis of azamacrocycles via a Mitsunobu reaction

Article abstract of DOI:10.1016/j.tetlet.2005.04.078

Reaction of pernosylated diethylenetriamine and 2-substituted propane-1,3-diols in dry THF in the presence of triphenylphosphine and diisopropyl azodicarboxylate gives the corresponding protected 9-substituted 1,4,7-triazacyclodecanes. The Mitsunobu reaction was also used in the preparation of 3-substituted 1,5,9-triazacyclododecanes and macrocyclic pyridine derivatives.

Full text of DOI:10.1016/j.tetlet.2005.04.078

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4387–4389
Synthesis of azamacrocycles via a Mitsunobu reaction
Jari Hovinena,* and Reijo Sillanpaab
¨ ¨
aPerkinElmer Life and Analytical Sciences, Turku Site, PO Box 10, FIN-20101 Turku, Finland
bDepartment of Chemistry, University of Jyva¨skyla¨, FIN-40351 Jyva¨skyla¨, Finland
Received 17 February 2005; revised 12 April 2005; accepted 19 April 2005
Available online 5 May 2005
Abstract—Reaction of pernosylated diethylenetriamine and 2-substituted propane-1,3-diols in dry THF in the presence of triphen-
ylphosphine and diisopropyl azodicarboxylate gives the corresponding protected 9-substituted 1,4,7-triazacyclodecanes. The Mit-
sunobu reaction was also used in the preparation of 3-substituted 1,5,9-triazacyclododecanes and macrocyclic pyridine derivatives.
Ó 2005 Elsevier Ltd. All rights reserved.
The metal chelates of azamacrocycles are widely used as
radiopharmaceuticals1 and MRI contrast agents.2 They
also have diagnostic applications.3 Furthermore, euro-
pium(III) chelates based on 1,4,7-triazacyclododecane
are among the brightest stable lanthanide(III) chelates
synthesized.4,5 Azacrown-functionalized oligonucleo-
tides are potential artificial RNases.6,7
Nosylamides are known to react with secondary and pri-
mary alcohols under standard Mitsunobu conditions
giving the corresponding alkylated sulfonamides in
15,16
excellentyield.
The reaction has also been success-
fully employed for the preparation of cyclic amines.17
Thus, it was interesting to discover if the Mitsunobu
reaction could be exploited for a one-pot preparation
of azamacrocycles, simply by controlling the molecular
ratio of the reactants. Accordingly, the amide 18 was
treated with an equimolar amount of various propane-
1,3-diols (2a–c) in the presence of triphenylphosphine
and diisopropyl azodicarboxylate (DIAD) in dry
THF18 (Scheme 1).
Most commonly, azamacrocycles are synthesized via the
method of Richman and Atkins.8 According to the latest
modification of this reaction, the synthesis involves a
reaction between a bifunctional electrophile (e.g., a di-
bromide or ditosylate) and a pernosylated amine in
dry DMF at an elevated temperature in the presence
of cesium or sodium carbonate.9–11 Finally, the nosyl
groups are removed with a thiol in the presence of base
giving the desired azamacrocycle.
The reactions were complete in few hours at room
temperature. After isolation by a silica gel column
For several applications, such as for biomolecule conju-
gation, synthesis of carbon-substituted azacrowns with a
reactive x-substituent is needed. Although this type of
molecule can be synthesized according to the method
of Richman and Atkins,12 alternative, simpler proce-
dures are desirable. An elegant method for the prepara-
tion of azacrowns via orthoamides has been described,13
but it is limited to the synthesis of 3-substituted 1,5,9-
triazacyclododecanes.6,7,14 Furthermore, the drastic
conditions for orthoamide hydrolysis limit the nature
of the tethering group.
R
R
R
Ns
H
Ns
H
N
N
Ns
OH
NH HN
HO
2a-c
Ns
N
thio-
N
phenol
N
H
N
N
Ph3P/ DIAD
Ns
1
K2CO3
Ns
4a,d,e
3a-c
a: R = H (53%)
b: R = CH2OTr (78%)
TFA
c: R = (CH2)3OMMTr (61%)
d: R = CH2OH
TFA
O2N
e: R = (CH2)3OH
O
Ns =
S
Keywords: Mitsunobu reaction; Azacrown; Azamacrocycle.
*
O
Corresponding author. Tel.: +358 2 2678 513; fax: +358 2 2678
380; e-mail: jari.hovinen@perkinelmer.com
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.078

4388
J. Hovinen, R. Sillanpa¨a¨ / Tetrahedron Letters 46 (2005) 4387–4389
OTr
Ns
Ns
1
x
N
N
OTr
Ph3P/ DIAD
N
OH
HO
Ns
7
5
R
R
N
N
N
1
Ns
N
N Ns
Ph3P/ DIAD
Ns
OH
OH
6a,b
8a (68 %)
8b (71%)
a: R = Br
TrO
b: R = O(CH2)4(C6H4)-p-NO
2
Figure 1. Thermal ellipsoid plotof 3b. 3CHCl3 drawn athte 30%
probability level. Chloroform molecules are omitted for clarity.
Ns
Ns
Ns
Ns
N
N
NH HN
2b
N
N
Ph3P/ DIAD
72%
Ns
chromatography, the products were characterized as 3a–
c, based on their MS and H NMR spectra. Further-
Ns
1
10
9
more, compound 3a was chromatographically identical
with material synthesized according to the latest modifi-
cation of the method of Richman and Atkins, and com-
pound 3b gave crystals that enabled determination of
the molecular structure by X-ray diffraction as 3b.
3CHCl3 (Fig. 1).19 It is worth noting that preparation
of 3b,c from 1 and the ditosylates of 2b,c in DMF in
the presence of Cs2CO3 were not successful. By contrast,
in the Mitsunobu reaction, the highest yield (78%) was
obtained using 2b, a diol with a bulky trityl group in
close proximity to the reaction centers. The azacrowns,
4,20 were isolated as their hydrochlorides after removing
the protecting groups according to standard literature
procedures.
Scheme 2.
OCH2SCH3
Ns
Ns
N
N
DMSO
3d
N
Ac2O, HOAc
69%
Ns
11
O
Ns
N
N
N
O
N
Ns
The applicability of the Mitsunobu reaction to the prep-
aration of other types of macrocycle was tested by
allowing 1 to react with 3-(trityloxy)-propane-1,2-diol
5 and 4-substituted pyridine-2,6-dimethanols, 6a21 and
6b22 (Scheme 2). While an attempt to synthesize 7 was
unsuccessful, compounds 8a,b were obtained in moder-
ate yields.23 Also, the reaction between pernosylated
dipropylenetriamine, 9,8 and 2b yielded the desired aza-
macrocycle, 10.
N
DMTrO
5´-DMTr-dU
Ns
O
3e
Ph3P/ DIAD
82%
OH
12
Scheme 3.
types of azacrown and macrocyclic pyridine derivatives.
The diol counterpart must have two primary hydroxy
groups in its structure. Bulky substituents in close prox-
imity to the reaction centers seem to facilitate the
reaction.
When desired, the macrocycles synthesized can be easily
converted to other derivatives. Two examples are shown
in Scheme 3. Accordingly, treatment of 3d with a mix-
ture of DMSO, acetic acid, and acetic anhydride
(5:1:2; v/v/v) overnightatan ambientetmperaut re gave
the corresponding methylthiomethyl ether, 11, a versa-
tile intermediate for further derivatizations.24,25 Com-
pound 3e, in turn, was converted to a nucleoside
derivative, 12, via a Mitsunobu reaction with 20-deoxy-
50-O-(4,40-dimethoxytrityl)-uridine.26
References and notes
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reaction is described. As demonstrated, the cyclization
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4.06 (2H, m); 3.78 (3H, s); 3.61 (4H, m); 3.37 (2H, m);
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1
(0.66 g,
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(0.79 g, 3.0 mmol) were dissolved in dry THF (25 mL).
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during 15 min, and the reaction was allowed to proceed at
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