Nucleophilic reactivity of perhydro-3,6,9,12-tetraazacyclopenteno[ 1,3- f,g]acenaphthylene. A unified approach to N-monosubstituted and N,N''- disubstituted cyclene derivatives

Article abstract of DOI:10.1016/S0040-4039(99)02262-5

Perhydro-3,6,9,12-tetraazacyclopenteno[1,3-f,g]acenaphthylene is readily mono- and dialkylated on nitrogen with alkyl bromides and iodides giving mono- and bis-quarternary ammonium salts. The title compound is a unified starting material for the preparation of cyclene based chelators. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02262-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1249–1253
Nucleophilic reactivity of perhydro-3,6,9,12-
tetraazacyclopenteno[1,3-f,g]acenaphthylene. A unified approach
to N-monosubstituted and N,N00-disubstituted cyclene derivatives
Jan Rohovec, Robert Gyepes, Ivana Císaˇrová, Jakub Rudovský and Ivan Lukeš ∗
Department of Chemistry, Faculty of Science, Charles University, Albertov 2030, 128 40, Prague 2, Czech Republic
Received 23 September 1999; revised 1 December 1999; accepted 7 December 1999
Abstract
Perhydro-3,6,9,12-tetraazacyclopenteno[1,3-f,g]acenaphthylene is readily mono- and dialkylated on nitrogen
with alkyl bromides and iodides giving mono- and bis-quarternary ammonium salts. The title compound is a unified
starting material for the preparation of cyclene based chelators. © 2000 Elsevier Science Ltd. All rights reserved.
Cyclene derivatives are widely investigated chelators due to their biomedical applications. The synthe-
sis of derivatives with differentiated sidearms on nitrogen has been addressed so far by stepwise closure
of the macrocyclic ring, starting from appropriately alkylated non-cyclic materials,1 or by pH-controlled
N-alkylation of an excess of free cyclene with a less than stoichiometric amount of reactive halide,1,2
with careful pH control. These methods suffer from only moderate yields and long separation steps.
Procedures for obtaining monoalkyl-substituted cyclenes are based on the concept of cyclene protection
with silicon, phosphoryl or tricarbonylmolybdenum groups, affording N-alkylated cyclenes with CxHy
(x=1,2,3, y=2x+1) groups on nitrogen.3
Recently, a special case of protection of the cyclene ring by conversion to glyoxal aminal 1 was used by
Weisman in the synthesis of 4,10-dibenzyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane,4 while Baker et al.
used this type of protection in the conversion of N-monoethyl to N-monooctadecyl cyclene.5 However, the
reaction leading to methyl or benzyl derivatives resulted in a mixture of mono- and dialkyl-compounds5
due to overalkylation. The aminal 1 was also utilised by Handel as a key intermediate in the synthesis
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02262-5
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of cyclene.6 The ready availability of 1 encouraged us to study its use in the synthesis of monoalkyl- or
N,N00-dialkyl-cyclene derivatives in detail. In the present paper we focused on the nucleophilic reactivity
of 1, as procedures for conversion of cyclic diaminals to cyclene derivatives are well established.7
We had observed that compound 1 smoothly reacts with alkyl iodides and bromides and various
other alkylating agents in toluene or acetonitrile as solvent at room temperature giving monoquarternary
ammonium salts 2–10 (Scheme 1, Table 1) in good to excellent yields.
Scheme 1. Reagents and conditions for monosubstitution of 1
Table 1
Monoquarternary ammonium salts of 1a
A typical procedure is given in Ref. 8. Choice of an appropriate solvent is essential for avoiding
dialkylation, which was not studied by Baker.5 The reaction of 1 with ethyl bromoacetate leads to a
valuable product in the synthesis of DOTA (i.e. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)
analogues. Toluene was found to be the solvent of choice for monoalkylation, as the monoquarternary
salts 2–10 are almost insoluble in the hydrocarbon, thus preventing dialkylation.
Prolonged action of excess of alkylating agents to 1 leads to formation of N,N00-disubstituted products,
as was known4 for R1=PhCH2. We observed that other selected alkylating agents showed the same
behaviour, forming products 12–18 (Scheme 2, Table 2).
Scheme 2. Reagents and conditions for N,N00-dialkylation of 1
Acetonitrile proved to be a suitable solvent for N,N00-dialkylation. Under the reaction conditions used,
N,N0-substitution was not observed in any case, probably due to repulsion of positive charges in adjacent

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Table 2
Symmetrical bisquarternary ammonium salts of 1a
positions in the macrocyclic ring. The triple alkylation does not proceed, not even with high excesses of
highly reactive alkyl iodide (e.g. CH3I, CH3I:1 molar ratio 10:1), at prolonged reaction times (two weeks
at room temperature). The room temperature reaction was found to give purer products than the reaction
carried out at 60°C. A representative procedure is given in Ref. 10. The products 5, 6, and 7 were found
to undergo a second alkylation with a different alkylating agent in acetonitrile as a solvent according
to Scheme 3 and Table 3, providing that they are at least slightly soluble in the reaction medium. The
reaction conditions are the same as for preparation of 12–18.10
Scheme 3. Reagents and conditions for preparation of unsymmetrical N,N00-dialkyl derivatives of 1
Table 3
Unsymmetrical bisquarternary ammonium salts of 1a
Deprotection of the salts 2–24 upon formation of N-monoalkylated or N0,N00 dialkylated cyclene
derivatives was achieved according to established literature techniques by treatment with aqueous
sodium hydroxide, hydrazine monohydrate, or an ethanolic solution of hydroxylamine.5–7 Representative
procedures are described in Ref. 13, together with characterisation of products.
Compounds 5 and 14 were characterised by X-ray diffraction of a single crystal obtained by recrys-
tallisation of 5 from hot H2O (Fig. 1) or during the alkylation in the case of 14 (Fig. 2).The results fully
confirmed the structures of 5 and 14 obtained from 1H and 13C NMR measurements. Exclusive formation
of one isomer with a cis arrangement of the aminal bridge was found. Full experimental results, atomic
coordinates and e.s.d.s were deposited with the CCDC.

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Fig. 1. X-Ray structure of 5·H2O in P21, the final R value was 0.043
Fig. 2. X-Ray structure of 14 in C2/c, the final R value was 0.042
The driving force for the alkylation reaction discussed is separation of insoluble mono- or bis-
quarternary ammonium salts from solution during the course of the alkylation. The procedure described
represents a unified, easily accomplished and cheap route to mono- or N,N00-disubstituted cyclene
derivatives with various pendant arms. Starting from easily accessible 1, this procedure makes it possible
to obtain a variety of new of DOTA-type ligands.
Acknowledgements
This work was supported by grant of the Ministry of Education of the Czech Republic VS 96140 and
COST D8.
References
1. Dischino, D. D.; Delaney, E. J.; Emswiler, J. E.; Gaughan, G. T.; Prasad, J. S.; Srivastava, S. K.; Tweedle M. F. Inorg. Chem.
1991, 30, 1265–1268.
2. Kovacs, Z.; Sherry, A. D. J. Chem. Soc., Chem. Commun. 1995, 185–186; Weeks, J. M.; Taylor, M. R.; Wainwright, K. P. J.
Chem. Soc., Dalton Trans. 1997, 317–318; van Westrenen, J.; Sherry, A. D. Bioconjugate Chem. 1992, 3, 524–526.
3. Patinec, V.; Yaouanc, J. J.; Clement, J. C.; Handel, H.; des Abbayes, H. Tetrahedron Lett. 1995, 36, 79–82; Filali, A.;
Yaouanc, J. J.; Handel, H. Angew. Chem. 1991, 103, 563–564; Roignant, A.; Gardinier, I.; Bernard, H.; Yaouanc, J. J.;
Handel, H. J. Chem. Soc., Chem. Commun. 1995, 1233–1234.
4. Weisman, G. R.; Wong, E. H.; Hill, D. C.; Rogers, M. E.; Reed, D. P.; Calabrese, J. C. J. Chem. Soc., Chem. Commun. 1996,
947–948.
5. Baker, W. C.; Choi, M. J.; Hill, D. C.; Thompson, J. L.; Petillo, P. A. J. Org. Chem. 1999, 64, 2683–2689.
6. Herve, G.; Bernard, H.; LeBris, N.; LeBaccon, M.; Yaouanc, J. J.; Handel, H. Tetrahedron Lett. 1999, 40, 2517–2520.

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7. Sandnes, R. W.; Gacek, M.; Undheim, K. Acta Chim. Scand. 1998, 52, 1402–1404; Sanders, R. W.; Vasilevskis, J.; Undheim,
K.; Gacek, M. Patent WO96/28432, 1996.
8. Compound 2 (representative procedure): To a stirred solution of 0.19 g of 1 (1 mmol) dissolved in 1 ml of dry toluene a
solution of 0.14 g (1 mmol, 1 equivalent) of CH3I in 0.5 ml of dry toluene was added during 1 min. An exothermic reaction
proceeded and a precipitate was formed. After stirring for 1 h, the product was filtered off.
9. 13C NMR (D2O 25°C, ref. t-BuOH int.) 2: CH2 47.10, CH3 50.47, CH2 50.66, 50.84, 51.15, 51.30, 54.27, 64.15, 68.49, CH
74.61, 86.54; 3: CH3 11.09, CH2 46.68, 50.64, 50.68, 51.21, 51.43, 54.26, 56.96, 59.13, 64.40, CH 74.73, 86.43; 4: CH3
13.12, CH2 19.45, 46.71, 50.67, 50.81, 51.23, 51.45, 54.27, 59.87, 62.84, 65.04, CH 74.76, 86.57; 5: CH2 46.93, 50.61,
50.70, 51.30, 51.38, 54.36, 60.27, 64.36, 64.69, CH 74.79, 85.63, CHAr 132.66, 134.15, 135.57, CAr 129.91; 6: CH2 46.82,
50.63, 50.67, 51.27, 51.37, 54.38, 60.29, 63.26, 64.73, CH 74.72, 86.38, CHAr 127.61, 136.85, CAr 152.19; 7: CH3 16.23,
CH2 47.01, 50.70, 51.26 (double), 51.35, 54.29, 60.09, 62.37, 66.89, 67.53, CH 74.69, 87.64, CO 168.25; 8: CH2 47.02,
50.67, 51.31, 51.32, 51.39, 54.28, 60.28, 62.38, 67.67, CH 74.72, 87.40, CO 169.27; 9: CH2 24.18, 46.79, 50.68, 50.93,
51.23, 51.37, 54.29, 64.50, 61.45, 65.77, CH 74.70, 86.72; 10: CH2 21.08, 46.62, 50.54, 50.71, 51.11, 51.30, 54.23, 57.20,
60.23, 60.35, 65.27, CH 74.53, 87.29. All the compounds gave satisfactory elemental analysis.
10. Compound 12 (representative procedure): To a stirred solution of 0.19 g of 1 (1 mmol) in 1 ml of dry acetonitrile, 0.45 g
(3 mmol, 3 equivalents) of CH3I was added in one portion. An exothermic reaction proceeded and a precipitate was formed.
The product was filtered off after 1 h. For less reactive bromides and long chain alkyl iodides, prolonged reaction times were
used.
11. 13C NMR (D2O 25°C, ref. t-BuOH int.) 12: CH2 46.02, CH3 49.78, CH2 49.45, 62.09, 67.94, CH 80.99; 13: CH3 11.06,
CH2 45.72, 49.31, 56.67, 57.36, 64.04, CH 81.35; 14: CH3 13.08, CH2 19.41, 45.74, 49.41, 58.21, 62.34, 64.61, CH 81.31;
15: CH2 45.86, 49.10, 57.87, 63.98, 64.15, CH 80.67, CHAr 135.48, 132.80, 134.41, CAr 129.25; 16: CH2 45.37, 48.96,
58.03, 62.94, 64.49, CH 81.30, CHAr 127.57, 136.05, 136.63, CAr 152.29; 17: CH3 16.04, CH2 45.83, 49.86, 59.35 (double),
60.27, 66.93, CH 81.94, CO 167.7; 18: CH2 46.07, 50.09, 59.83, 60.59, 67.23, CH: 81.94, CO 168.67. All the compounds
gave satisfactory elemental analysis.
12. 13C NMR (D2O, 25°C, ref. t-BuOH int.) 19: CH2 45.77, 46.04, 49.12, 49.41, CH3 49.56, CH2 57.85, 62.11, 63.89, 64.17,
67.93, CH 80.41, 81.99, CHAr 132.78, 134.35, 135.47 CAr 132.14; 20: CH2 45.55, 45.92, 49.15, 49.31, CH3 49.77, CH2
60.39, 62.04, 62.54, 64.17, 67.87, CH 80.81, 80.96, CHAr 127.72, 136.88, CAr 136.08, 151.98; 21: CH3 16.28, CH3N 49.73,
CH2 45.89, 46.01, 49.45, 49.99, 59.67, 60.55, 61.95, 67.05, 67.10, 67.96, CH 80.90, 82.16, CO 167.59; 22: CH3 16.25,
49.67 CH2 45.90, 46.13, 49.46, 50.01, 59.65, 60.58, 61.96, 67.10, 67.12, 67.15, 67.99 CH 80.97, 82.21, CO 167.65; 23: CH3
16.25 CH2 45.95 (double), 49.17, 50.01, 57.79, 59.53, 60.67, 63.98, 64.21, 67.13 (double), CH 80.36, 82.42, CHAr 132.80,
134.43, 135.48, CAr 129.20, CO 167.77; 24: CH3 16.23 CH2 45.77, 45.85, 49.18, 49.95, 57.69, 60.61, 62.74, 64.35, 67.02,
67.08, 67.15, CH 81.19, 82.23, CHAr 127.71, 136.79 CAr 136.13, 152.33, CO 167.74. All the compounds gave satisfactory
elemental analysis.
13. Monomethylcyclene tetrahydrochloride (representative procedure, deprotection with NH2OH): Compound 2 (0.25 g, 0.75
mmol) was dissolved in 10 parts of 2 M solution of NH2OH in dry EtOH. A slightly exothermic reaction proceeded. After
refluxing for 2 h, the solution was mixed with an equal volume of 10% KOH and extracted five times with dichloromethane.
Evaporation of the extracts and acidification with aqueous HCl gave a product identical with the authentic sample prepared
by the Ritchman–Atkins procedure (0.22 g, 89%). 13C NMR (D2O 25°C, ref. t-BuOH int.) CH3 44.96, CH2 45.27, 46.11,
46.73, 55.43. Similarly, 1,7-dimethylcyclene tetrahydrochloride (0.14 g, 77%,13C NMR (D2O 25°C, ref. t-BuOH int.) CH3
45.35, CH2 45.47, 55.09) and 1,7-dibenzylcyclene tetrahydrochloride (0.20 g, 86%,13C NMR (D2O 25°C, ref. t-BuOH int.)
CH2 45.51, 50.98, 60.65, CHAr 131.67, 132.80, 133.08, CAr 138.55) from 12 and 15 were prepared. Monobenzylcyclene
tetrahydrochloride (representative procedure, deprotection with NH2NH2): Compound 5 (1,15 g, 3.14 mmol) was dissolved
in 6 ml of hydrazine monohydrate and heated (100°C) for 24 h. The excess of hydrazine was evaporated, the product was
extracted four times with hexane. Evaporation of the extracts and acidification with azeotropic HCl gave a crude product,
which was purified by crystallisation from water ( 0.77 g, 60%) 13C NMR (D2O 25°C, ref. t-BuOH int.) CH2 37.48, 37.57,
39.31, 43.72, 52.73, CHAr 124.16, 124.51, 125.63, CAr 129.28.