Expeditious N-monoalkylation of 1,4,7,10-tetraazacyclododecane (cyclen) via formamido protection

Article abstract of DOI:10.1016/S0040-4039(00)01092-3

The reaction of cyclen 1 with chloral hydrate afforded exclusively 1,4,7-triformylcyclen 2 in high yield; the triprotected macrocycle was easily alkylated with various electrophiles in good to excellent yields. The alkaline removal of the formyl groups pr

Full text of DOI:10.1016/S0040-4039(00)01092-3

Tetrahedron Letters 41 (2000) 6527±6530
Expeditious N-monoalkylation of 1,4,7,10-
tetraazacyclododecane (cyclen) via formamido protection
Vincenzo Boldrini,a Giovanni B. Giovenzana,b Roberto Pagliarin,a
Giovanni Palmisanoc and Massimo Sistic,*
aDipartimento di Chimica Organica e Industriale, Via Venezian, 21-20133 Milano, Italy
bDipartimento di Scienze Chimiche Alimentari Farmaceutiche e Farmacologiche, V. le Ferrucci 33,
28100 Novara, Italy
cDipartimento di Scienze Chimiche, Fisiche e Matematiche, Via Lucini, 3-22100 Como, Italy
Received 19 June 2000; accepted 29 June 2000
Abstract
The reaction of cyclen 1 with chloral hydrate a€orded exclusively 1,4,7-triformylcyclen 2 in high yield;
the triprotected macrocycle was easily alkylated with various electrophiles in good to excellent yields. The
alkaline removal of the formyl groups provided a selective entry into N-monosubstituted cyclen derivatives.
# 2000 Elsevier Science Ltd. All rights reserved.
Since the discovery of the Gd(III) complex of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-
tetraacetic acid) as an ecient contrast agent (CA) for magnetic resonance imaging (MRI),1
intensive research in this area has led to several related compounds entering late phase clinical
trials and the marketplace.2 Current CAs often have severe adverse e€ects (limited sensitivity due
to poor tissue selectivity) so that more ecient and selective agents are being actively sought. One
approach relies on the feasibility of tuning the lipophilicity of the ligands2,3 by replacing a
CH2COOH moiety of DOTA with an appropriate alkyl group (e.g., HP-DO3A, DO3A-butrol)2b
while maintaining high relaxation enhancement and modifying the biodistribution of metal
complex-based drugs.
From a synthetic point of view, N-monoalkylated cyclen derivatives represent the key
intermediates for the synthesis of DOTA-like ligands. Selective monoalkylation of cyclen can be
run using two main strategies, i.e., direct alkylation of an excess of cyclen with the appropriate
alkyl halide4 or selective N-functionalization5 followed by alkylation±deprotection steps.
Although conceptually straightforward, the implementation of such strategies in an ecient and
practical manner constitutes a demanding challenge in synthetic methodology.
By exploiting the ®nding that some acylating reagents (e.g. Cbz-Cl, Boc2O)6 a€ord under
strictly controlled conditions mainly triprotected cyclen, we report here that triformylcyclen 2,
* Corresponding author. E-mail: sistimax@icil64.cilea.it
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01092-3

6528
exclusively obtained from 1 in excellent yield, represents a key intermediate to N-monosubstituted
cyclen derivatives (Scheme 1).
Scheme 1. (i) CCl3CH(OH)2, EtOH, 60ꢀC; (ii) R±X, DMF, K2CO3, 80ꢀC; (iii) 0.2 M NaOH, 80ꢀC
Thus, compound 2 was prepared by reacting 1 (10 mmol) with commercially available chloral
hydrate7 (60 mmol) in ethanol (15 ml) at 60ꢀC for 3 h. Fully or partially formylated derivatives
were completely absent (by ESI-MS) from the reaction mixture even if the reaction was
performed with a large excess of the reagent (up to 100 mmol). The usual workup followed by
silica gel ®ltration (CH2Cl2:MeOH:NH3, 9:1:0.1) a€orded pure compound 2 in 92% yield. The
reaction proceeded less satisfactorily in H2O giving rise to 2 in 52% yield. Other formylating
agents such as methyl or ethyl formate or formic acid8 were tested but they proved less ecient in
terms of chemical yields (20±35%) and longer reaction times (3 days at re¯ux with alkyl formates,
2 days at 100ꢀC with formic acid). Owing to a hindered rotation of the N±CHO bonds, the NMR
resonances appear as broad signals in the 1H and 13C NMR spectra and the structure of compound 2
was ascertained by HR-MS and elemental analysis. VT-NMR in DMSO-d6 displayed coalescence
of the CHO signals at 400 K. In justifying the experimental results, i.e. the exclusive formation of
a triformyl derivative, we can only speculate that at least one basic nitrogen atom is required to
assist intramolecularly the formylation reaction, possibly by general base catalysis. This hypothesis
was supported by the isolation of tetraformylcyclen when either 1 or 2 was reacted with chloral
hydrate in neat triethylamine.
The subsequent alkylation of 2 was performed with the appropriate electrophile in DMF at
80ꢀC and in the presence of anhydrous K2CO3. It is remarkable that the monoalkylated products
3 were obtained in good to excellent yields even with long-chain alkyl halides (Table 1).
Table 1
Alkylation of triformylcyclen 2 with various electrophiles

6529
The interest in the synthesis of polymacrocyclic ligands6b,9 prompted us to check the reactivity
of 2 towards polyelectrophiles [e.g., 1,3-bis(bromomethyl)benzene, 1,4-bis(bromomethyl)benzene,
1,3,5-tris(bromomethyl)benzene] (Fig. 1).
Figure 1.
We found that the best experimental conditions to perform the alkylation of 2 with these
reagents required the use of anhydrous MeCN and K2CO3 as the base under re¯ux for 3 days. In
this way, we could isolate compounds 5a±7a in satisfactory isolated yields (73, 68 and 60%,
respectively, after silica gel chromatography). By employing DMF as solvent in the alkylation
step at 80ꢀC, we could not avoid formation of the alcohol 8 arising from hydrolysis of the
mono(bromomethyl) intermediate.
Once the alkylation products 3a±i, 5a±7a were isolated, conversion to the corresponding
N-monoalkylated compounds 4a±i, 5b±7b was accomplished by treatment with 0.2 M NaOH at
80ꢀC for 4 h with yields ranging from 85 to 95%. The free bases were characterized by 1H NMR,
13C NMR and MS spectra which were in full agreement with literature data.5a,6b,9a
The commercial availability of chloral at low cost combined with the operational simplicity
and the complete selectivity makes this methodology extremely attractive for the synthesis of
N-monoalkylated cyclen derivatives and polycyclen analogues. Furthermore, the protective step
proceeded under neutral conditions and without exclusion of air and moisture, which is a
signi®cant improvement over current procedures.
Acknowledgements
This work was supported by CNR, Rome, through Target project on `Biotechnology'. Professor
S. Aime (University of Turin) is gratefully acknowledged for his interest and helpful discussions.
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