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Synlett 2012(6): 893-896  
DOI: 10.1055/s-0031-1290616
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Alkylation of Cyclic Amines with Arginine-Modified Electrophiles

Mojmír Suchýa,b, Robert H. E. Hudson*a
a Department of Chemistry, The University of Western Ontario, London, ON, N6A-5B7, Canada
Fax: +1(519)6613022; e-Mail: rhhudson@uwo.ca;
b Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario, London, ON, N6A-5K8, Canada
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Publikationsverlauf

Received 14 December 2011
Publikationsdatum:
15. März 2012 (online)

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Abstract

Previously, the outcome of the alkylation of cyclen (1,4,7,10-tetraazacyclododecane) with arginine-modified electrophiles was found to be dependent on the solvent used for the reaction as well as on the structure of the electrophile. Herein, we report the alkylation of the related nitrogen macrocycles, TACN (1,4,7-triazacyclononane), cyclam (1,4,8,11-tetraazatetradecane) and the smaller cycles piperidine and piperazine with arginine-modified electrophiles. The products of peralkylation predominate for piperazine and TACN while the product of trialkylation is isolated as a sole product, when cyclam is used as a substrate for the alkylation. The results reported herein provide useful information for chemists involved in the design and synthesis of ligands for MRI (magnetic resonance imaging) contrast agents and for PET (positron emission tomography) imaging agents.

Key words

arginine - piperidine - piperazine - TACN - cyclam - cyclen - PET - MRI - polyazamacrocycle

    References and Notes

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8

General Experimental Procedures: All amino acids (naturally occurring l-isomers) and reagents were commercially available, unless otherwise stated. All solvents were HPLC grade and used as such, except for H2O (18.2 MΩ˙cm-¹ Millipore water). Organic extracts were dried with Na2SO4 and solvents were removed under reduced pressure in a rotary evaporator. Aqueous solutions were lyophilized. Flash column chromatography (FCC) was carried out using silica gel, mesh size 230-400 Å. Thin layer chromatography (TLC) was carried out on Al-backed silica gel plates, compounds were visualized by UV light or I2 vapors. HPLC analysis and purification were done using a Delta-Pak C18 300 Å column (particle size 15 µm; 8 × 100 mm Radial-Pak cartridge). Mobile phase: method A: 90% H2O-10% MeCN → 50% H2O-50% MeCN over 9 min (compounds 7a, 7b, 11a and 11b); method B: 90% H2O-10% MeCN → 59% H2O-41% MeCN over 7 min, fractions containing an impure material were concentrated and subjected to the purification using method C: 99% H2O-1% MeCN → 89% H2O-11% MeCN over 11 min (compounds 10a and 10b). Linear gradient and flow rate 3 mL/min was used in all the methods listed above. Ultra performance liquid chromatography (UPLC) was performed using a BEH C18 column (particle size 1.7 µm; 2.1 id × 50 mm) with an inline mass detector. Mobile phase: method D: 100% H2O → 25% H2O-75% MeCN over 3 min, linear gradient, flow rate 0.25 mL/min. NMR spectra were recorded on 400 MHz spectrometer; δ values were referenced as follows DMSO-d 6 (2.49 ppm) for ¹H NMR (400 MHz) and DMSO-d 6 (39.5 ppm) for ¹³C NMR (100 MHz). Mass spectra (MS) were obtained using an electron spray ionization (ESI) Time-of-Flight (TOF) instrument.

9

Supporting Information: General considerations and experimental procedures for the preparation of compounds 9a, 9b, 10a, 10b, 11a and 11b; ¹H NMR spectra of compounds 7a, 7b, 9a, 9b, 10a, 10b, 11a and 11b; ¹³C NMR spectra of compounds 9a and 9b; high resolution (ESI) mass spectra of compounds 7a, 7b, 10a, 10b, 11a and 11b.

13

Alkylation of TACN (7a) with N -Chloroacetyl-Gly-Arg(NO 2 )-OMe (3a) and N -Chloroacetyl-Arg(NO 2 )-OMe (4a), a Representative Experimental Procedure:
N-chloroacetyl-Gly-Arg(NO2)-OMe (3a; 139 mg, 0.38 mmol) and N-chloroacetyl-Arg(NO2)-OMe (4a; 117 mg, 0.38 mmol) and were added to separate solutions of TACN (7a; 16 mg, 0.13 mmol) and DIPEA (66 µL, 0.38 mmol) in MeCN (1.8 mL) and DMF (200 µL). The mixtures were stirred for 24 h at 70 ˚C, MeCN was evaporated, the residues were dissolved in MeOH-H2O (1.5 mL each) and were subjected to semi-preparative HPLC purification. The fractions containing the products were concentrated to afford the products as colorless solids. NOTAM-Gly-Arg(NO2)-OMe (7b): yield: 104 mg (74%). HPLC (method A): t R = 5.5 min. ¹H NMR (DMSO-d 6): δ = 8.46 (br s, D2O exch., 5 H), 7.91 (br s, D2O exch., 5 H), 4.27 (m, 3 H), 3.80 (m, 6 H), 3.62 (m, 15 H), 3.09 (m, 18 H), 1.61 (m, 12 H). HRMS (ESI): m/z [M + H]+ calcd for C39H70N21O18: 1120.5208; found: 1120.5176. NOTAM-Arg(NO2)-OMe (7c): yield: 87 mg (73%). HPLC (method A): t R = 5.6 min. ¹H NMR (DMSO-d 6): δ = 8.56 (br m, D2O exch., 6 H), 7.91 (br s, D2O exch., 6 H), 4.29 (m, 3 H), 3.63 (s, 9 H), 3.59 (m, 6 H), 3.03 (m, 18 H), 1.64 (m, 12 H). HRMS (ESI): m/z [M + H]+ calcd for C33H61N18O15: 949.4564; found: 949.4559.

15

Initial attempts to metallate 7b and 7c under the previously established reaction conditions of heating an aqueous solution of Ga(NO3)3 at pH 3 (ref. 11) showed the reaction to be sluggish. After 18 h of reaction, the metallation was found to be ca. 10% complete by UPLC HRMS analysis. Considering the short half-lives of some radioactive isotopes of gallium, further optimization of the reaction conditions is mandated.