An Improved Synthesis of 1,4,7-Triazacyclononanes (tacns) and 1,4,7,10-Tetraazacyclododecanes (cyclens)

Huang Jianying. Zhou Zhongyuan. Chan TakHang. Synthesis  2009,  2341 

In the reaction of compound 7 with ethylenediamine (13) according to Scheme 4, it was reported that 1-tosyl-1,4,7-triazacyclononane (9) was obtained in 78% isolated yield. However, after being alerted by other laboratories, we repeated the same reaction under identical experimental conditions and did not obtain compound 9 as the product of the reaction. While the compound obtained was isomeric with 9 according to its mass spectrum, its 1H NMR spectrum was similar but not identical to that of 9, a known compound which could be obtained by an alternate route and independently synthesized according to Scheme 2.^¹ More significantly, the 13C NMR spectrum of the obtained product has four aromatic and five aliphatic carbon signals and is distinctly different from that of 1-tosyl-1,4,7-triazacyclononane (9) which has eight carbon signals. The product is assigned to have the structure 1-(2′-aminoethyl)-4-tosylpiperazine (23) (revised Scheme 4). The formation of a six-membered ring is consistent with the reaction of 7 with N,N-dimethylethylenediamine (10) in giving 1-methyl-4-tosylpiperazine (11) as we had reported in Scheme 3.

Revised Scheme 4: Reaction of 7 with 13

We also re-examined the coupling of 7 with 1,4,7-triazaheptane (19) using potassium carbonate in refluxing acetonitrile (Scheme 7). The product obtained was found not to be 1-tosyl-1,4,7,10-tetraazacyclododecane (20), a known compound independently synthesized by an alternate route.^² While the product was isomeric with 20 according to its mass spectrum, its ^¹H and ^¹³C NMR spectra were different from those of 20. The product is consistent with a piperazine structure 24, with four aromatic and six aliphatic carbon signals in its ^¹³C NMR spectrum (revised Scheme 7).

Revised Scheme 7: Reaction of 7 with 19

In conclusion, ethylenediamine (13) and 1,4,7-triazaheptane (19) did react with 7 but did not give the corresponding tacn 9 or cyclen 20.

1-(2′-Aminoethyl)-4-tosylpiperazine (23)

Compound 7 (5.83 g, 10.0 mmol), K₂CO₃ (8.00 g, 58.0 mmol), ethylenediamine (0.60 g, 10.0 mmol) and anhydrous MeCN (50 mL) were added to a round-bottom flask. The mixture was heated to reflux under an N2 atmosphere for 12 h. The mixture was cooled to r.t. and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (SiO₂, CH₂Cl₂-MeOH-Et₃N = 2:1:0.05 as eluent) to give 23 as a pale yellow oil (2.0 g, 78%).

^¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, J = 7.4 Hz, 2 H), 7.32 (d, J = 7.4 Hz, 2 H), 3.01 (br, 4 H), 2.73 (t, J = 6.0 Hz, 2 H), 2.52 (br t, 4 H), 2.43-2.40 (m, 5 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 143.7, 132.4, 129.6, 127.8, 60.2, 52.2, 46.0, 38.4, 21.5.

LRMS (ESI): m/z = 284 ([M⁺ + H], 100).

HRMS (ESI): calcd for C₁₃H₂₂N₃O₂S (M⁺ + H); 284.1433; found: 284.1423.

1-(1′,4′-Diazahexyl)-4-tosylpiperazine (24)

1,4,7-Triazaheptane (19, 0.40 g, 4.00 mmol), compound 7 (2.30 g, 4.00 mmol), K₂CO3 (6.00 g, 40.0 mmol) and anhydrous MeCN (20 mL) were added to a round-bottom flask. The mixture was heated to reflux under an N₂ atmosphere for 18 h. The mixture was cooled to r.t. and filtered. The filtrate was concentrated and the residue was purified by chromatography (SiO₂, CH₂Cl₂-MeOH = 2:1 as eluent) to give a light yellow oil (1.2 g, 83%).

^¹H NMR (400 MHz, CDCl₃): δ = 7.58 (d, J = 8.0 Hz, 2 H), 7.27 (d, J = 8.0 Hz, 2H), 2.95 (br, 4 H), 2.70 (t, J = 6.0 Hz, 2 H), 2.59 (p, J = 6.0 Hz, 2 H), 2.47 (br t, 4 H), 2.43 (t, J = 6.0 Hz, 2H), 2.37 (s, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 143.7, 132.4, 129.6, 127.8, 57.4, 52.3, 52.2, 46.1, 46.0, 41.4, 21.5.

LRMS (ESI): m/z = 327 ([M⁺ + H], 100), 349 ([M⁺ + Na], 29).

HRMS (ESI): calcd for C₁₅H₂₇N₄O₂S [M⁺ + H]: 327.1855; found: 327.1856.

Acknowledgment

We gratefully acknowledge the help of Dr. Kin-Fai Chan for repeating the experiments.

References

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(2) Compound 20 could be obtained by mono-tosylation of commercially available 2. See: (a) Ohashi, M.; Konkol, M.; Del Rosal, I.; Poteau, R.; Maron, L.; Okuda, J. J. Am. Chem. Soc., 2008, 130, 6920. (b) Leivers, M.; Breslow, R. Bioorg. Chem., 2001, 29, 345.