Short and straightforward synthesis of 1,7-dimethyl-1,4,7,10-tetraazacyclododecane

Article abstract of DOI:10.1016/j.tetlet.2010.04.115

A novel, cost-effective, and efficient process for the synthesis of 1,7-dimethyl-1,4,7,10-tetraazacyclododecane 1 has been developed. The two-step process involved the selective conversion of commercially available cyclen to N1,N7-diethylcarbamate cyclen

Full text of DOI:10.1016/j.tetlet.2010.04.115

Tetrahedron Letters 51 (2010) 3436–3438
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Tetrahedron Letters
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Short and straightforward synthesis of 1,7-dimethyl-1,4,7,10-
tetraazacyclododecane
a,*
a
b
b
a,*
Giovanni Piersanti , Maria Antonietta Varrese , Vieri Fusi , Luca Giorgi , Giovanni Zappia
a
Department of Drug and Health Sciences, University of Urbino, P.zza Rinascimento 6, I-61029 Urbino, Italy
Institute of Chemical Sciences, University of Urbino, P.zza Rinascimento 6, I-61029 Urbino, Italy
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel, cost-effective, and efficient process for the synthesis of 1,7-dimethyl-1,4,7,10-tetraazacyclodode-
cane 1 has been developed. The two-step process involved the selective conversion of commercially
available cyclen to N1,N7-diethylcarbamate cyclen 3 that afforded the title compound in high yield after
the reduction step.
Received 17 March 2010
Revised 24 April 2010
Accepted 27 April 2010
Available online 17 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Step economy
Selectivity
Cyclic tetramines
Reduction
DCM
In the past decade, step economy has become a fundamental
synthetic strategy for the construction of organic molecules and
it is a prominent goal of organic synthesis.1 A step-economical
synthesis has the potential to reduce the number and amount of
reagents employed by reducing the number of synthetic steps as
well as the length, waste, environmental impact, development
and execution time, separation science, effort, and cost. This should
also lead to an increase in chemical yield of the desired product,
and therefore the capacity to efficaciously deliver a meaningful
supply of the desired target, as well as speed, scientific advance-
ment, safety, return on investment, and most importantly human
economy. Traditionally, this has meant limiting the use of protect-
Me
N
HN
N
NH HN
NH HN
NH
Me
1
,7-Dimethylcyclen (DMC) (1) Cyclen (2)
Figure 1. The cyclic tetramines DMC 1 and cyclen 2.
In this context, 1,7-dimethyl-1,4,7,10-tetraazacyclododecane 1
Me2[12]aneN4), also called Dimethylcyclen (DMC), has received
considerable attention from the chemistry community, culminat-
ing recently in the discovery of its antitumor activity against HeLa
and A549 cell lines and its ability to hydrolyze double-strand DNA
(
1
0
2
ing group manipulations; now, judicious choice and development
of reactions or sequences of reactions allow for the step-economi-
cal synthesis of a given target structure.
1
0c,d
under physiological conditions (Fig. 1).
During our studies on the design, synthesis, and application of
novel molecular receptors for the molecular recognition and
Cyclic tetraamines have attracted increasing attention owing to
their versatile coordination properties which allow their use in
1
1
12
sensing of cations, anions, and neutral molecules, we have em-
ployed DMC 1 as a macrocyclic base upon which we built powerful
recognition systems by linking two identical side-arms containing
binding sites. More recently, the unsymmetrical difunctionaliza-
tion of 1 by an Ugi multicomponent reaction has been disclosed
3
many fields, especially for medical purposes. In particular, the
1
,4,7,10-tetraazacyclododecane (cyclen) 2 and its N-functionalized
4
derivatives have been extensively used and pursued since the
generated metal-chelates have wide applications as contrast
agents in MRI, radiodiagnostic and radiotherapeutic agents, fluo-
5
6
1
3
by us with the aim of preparing bifunctional chelating agents
BCAs) bearing different pendant arms, with potential novel radi-
odiagnostic and radiotherapeutic properties.
7
8
rescent sensors, molecular recognition, and catalysis compounds,
(
and as anti-HIV and anticancer agents (Fig. 1).9
There is clearly a strong need for an easy, practical, short, and
economical synthesis of DMC. The title compound has been
*
Corresponding authors. Tel.: +39 0722303320x41; fax: +39 0722303313 (G.P.).
E-mail addresses: giovanni.piersanti@uniurb.it (G. Piersanti), giovanni.zap-
pia@uniurb.it (G. Zappia).
14a
prepared for the first time by Micheloni and co-workers,
from
0
acyclic precursors by reacting the disodium salts of N -methyl-
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.115

G. Piersanti et al. / Tetrahedron Letters 51 (2010) 3436–3438
3437
0
0
N,N -bis(toluene-p-sulphonyl)diethylenetriamine, prepared in five
steps, with bis(2-chloroethyl)methylamine, obtained in three
steps, to give a protected form of the macrocyclic base. Removal
of the protecting groups gave the title compound in 30% overall
yield. Although this approach is currently used in practice, it is
too long and impractical to be used on a process scale. In addition,
the use of potentially dangerous chemicals renders this approach
environmentally unfriendly. More recently, two syntheses of
Table 1
Reagents and conditions for reduction step
Entry
Carbamate
Reducing agent
and conditions
Reduction
yield (%)
Overall
yielda (%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
LiAlH4 (1 M in THF), rt
54
35
75
65
15
49
28
68
59
14
LiAlH
LiAlH
4
(solid), THF, rt
(solid), THF reflux
4
Red-Al
Dibal-H
LiBH
BH THF, reflux
DMC (1) that rely upon a strategy of selective protection followed
b
4
NR
by methylation and deprotection have been reported.1
4b,c
Unfortu-
3
60
87
78
90
58
81
76
88
LiAlH
LiAlH
LiAlH
4
4
4
(solid), THF reflux
(solid), THF reflux
(solid), THF reflux
nately, both methods proved to be inefficient in terms of chemical
yield when 1 was prepared in large scale. However, deficiencies
associated with the available procedures clearly provide an oppor-
tunity for further process refinement.
Herein, we report a new, straightforward, step-economical, and
practical synthesis of 1 from commercial materials without using
any protecting groups. We envisioned a two-step process that
would allow rapid and selective access to 1. We assumed that
the N1 and N7 methyl groups might be introduced via conversion
of the appropriate carbamate system into methyl groups by hy-
dride reduction. The selective formation of N1,N7-bis-carbamates
10
Bold entries indicates the best result obtained.
a
From cyclen.
No reaction.
b
achieve reduction, we turned our attention to the reduction of
other bis-carbamate derivatives 3b–d with the aim of facilitating
product isolation and avoiding final purification by chromatogra-
4
phy. Thus, reaction of carbamate 3d with LiAlH in THF under
3
a–d was achieved in high yields by a slight modification of the
procedure developed by Kovacs and Sherry in order to scale up
refluxing conditions resulted in complete reduction of the carba-
mate moieties to give 1, after careful work-up of the reaction mix-
ture, in excellent yields (90%) as a pure compound judged by NMR
analysis. Under the same reaction conditions, compound 3c gave
comparable yields (87%), whereas the N1,N7-di Boc cyclen 3b gave
1
5
the reaction. Four different bis-carbamates 3a–d were prepared
in almost quantitative yields. More specifically, treatment of com-
mercially available cyclen 216 with various chloroformates under
acidic conditions (pH 2–3) resulted in the formation of 3a, 3c,
and 3d; while 3b was prepared using N-(tert-butoxycarbonyloxy)
succinimide in chloroform at room temperature (Scheme 1).
Although the conversion of a carbamate to a methyl group is
well documented in the literature17 by the use of different reduc-
ing reagents, only few examples of a contemporary double reduc-
tion have been reported.18
Table 1 reports the yields for the reduction of bis-carbamates
a–d to 1, using different reducing agents and conditions. In all
cases, the yields were from good to excellent, although significant
differences were observed. The first experiments were performed
using the N1,N7-di-Cbz derivative 3a, adding a commercially avail-
1
3
in only 78% yield. A scale-up of the reduction step to 50 mmole of
d gave 1 without any deleterious effect on the yield and selectiv-
19
ity. In conclusion, we have designed and executed a new, simple,
step-economical, two-step process for the preparation of the inter-
esting cyclic tetraamine 1,7-dimethyl-1,4,7,10-tetraazacyclodode-
cane 1 in 88% overall yield from commercially available cyclen.
We were able to make 1 with increasingly selective, efficient, prac-
tical, and environmentally friendly procedures. This original syn-
thetic procedure allows the easy and economical synthesis of
DCM 1 in sufficient quantities for the needs of various areas of
research.
3
able solution (1 M in THF, Aldrich) of LiAlH
4
(8 equiv) at 0 °C. After
Acknowledgments
3
h, most of the starting material was reduced, as judged by HPLC
and TLC analysis, and the reaction was stopped. The title com-
pound was isolated by neutral alumina chromatography purifica-
tion, in only 54% yield (entry 1). When the reaction was
Financial support from Università degli Studi di Urbino ‘‘Carlo
Bo” and M.I.U.R PRIN 2007, Italy, is gratefully acknowledged.
4
performed using a suspension of solid LiAlH (8 equiv) in THF un-
der refluxing conditions, the reaction went to completion and the
reduced compound was isolated in a gratifying 75% yield (entry
References and notes
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(
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3
(entry 7), but the yields were
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Cl
N
HN
N
Reducing
agents
N
HN
N
NH HN
NH HN
2
pH = 2-3
7
.
Then 30% NaOH (aq.)
NH
NH
for 3a,c,d
Ref.15c for 3b
O
Me
O
1
1
R
3
3
3
3
a = Bn
b = t-Bu
c = Me
d = Et
Scheme 1. Reaction sequence for the preparation of 1.

3
1
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added dropwise over 10 min from the dropping funnel (vigorous bubbling
upon addition). The resulting suspension was heated at reflux in a mineral oil
bath for 3 h. The reaction mixture was cooled to 0 °C (bath temperature) in an
ice-water bath and was diluted with ethyl ether (350 mL). Water (13.4 mL) was
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(LAH) necessitating slow addition of the water and cooling with a 0 °C ice-
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1
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a medium-
porosity, ceramic Büchner funnel lined with filter paper into a 100 mL filter
flask and was washed with diethyl ether (3 ꢂ 100 mL). The combined filtrates
were dried with anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure (25 °C, 10 mmHg) to afford the crude product as a brown
yellow oil. Water (35 mL) and chloroform (150 mL) were added. The layers
were separated and the aqueous solution was extracted with chloroform
(3 ꢂ 150 mL). The combined organic phase was washed with brine (100 mL),
the chloroform solution was dried with anhydrous sodium sulfate, and the
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4
7, 6937–6940.
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1
1
1
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clean 1,7-dimethyl-1,4,7,10-tetraazacyclododecane
1
(Me2[12]aneN4) as
1
13
judged by H, C NMR. An analytical sample was obtained by sublimation to
1
give a low melting point brown solid. Mp = 40–41 °C (lit. 41–42 °C Ref. 14a)1
NMR (200 MHz, CDCl3, 20 °C) d = 1.99 (s, 6H), 2.18 (bs, 8H), 2.31 (bs,8H)
H
C
3
1
9. 1,7-Dimethyl-1,4,7,10-tetraazacyclododecane (1): An oven-dried, 1 L, three-
necked, round-bottomed flask was equipped with a rubber septum, a 250 mL
pressure-equalizing addition funnel fitted with a rubber septum, a reflux
ꢀ
1
NMR (50 MHz, CDCl
2926, 2863, 1601, 1465, 1380 LRMS (ESI): C10
3
, 20 °C) d = 43.9, 44.7, 54.3 FT-IR (neat) cm : 3369, 3281,
: [M+H]: 201.1.
24 4
H N