a selective one-step synthesis of tris n-alkylated cyclens

A selective one-step synthesis of tris N-alkylated cyclensq

Cong Li and Wing-Tak Wong*

Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and

Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of China

Received 12 March 2004; revised 19 April 2004; accepted 22 April 2004

Abstract—A general one-step synthesis for tris N-alkylated cyclens with good yield and unprecedented selectivity is presented. Tris and 1,4-bis N-alkylated cyclens, as the only two major products are isolated. Furthermore, according to the single crystal X-ray structures of tris and1,4-bis N-alkylated cyclen 1 and 1a, one nitrogen atom on the cyclen ring can be protonated under this reaction condition, which prevents itsfurther alkylation, and gives rise to the regioselectivity ultimately.q 2004 Elsevier Ltd. All rights reserved.

1. Introduction

Ln3þ complexes that are based on multidentate 1,4,7,10-tetraazacyclododecane (cyclen) show high thermodynamicand kinetic stabilities in aqueous solution, and have beenwidely used as Magnetic Resonance Imaging (MRI)contrast agents (CAs),1 radio-pharmaceuticals,2 lumines-cence probes or switches,3 and RNA cleavers,4 etc. Forexample, the octacoordinate Gd3þ complex, [Gd-DOTA(H2O)]2 (Dotareme)5, is one of the most widely usedcontrast agents in clinics (Fig. 1). Compared to octacoordi-nate Ln3þ complexes, there has been a growing interest inmacrocyclic heptacoordinate Ln3þ complexes, especiallythe tris N-carboxymethyl-1,4,7,10-tetraazacyclodecane(DO3A) derivatives. Firstly, in DO3A derivatives, withthe exception of three pendant chelating moieties that areutilized for strong lanthanide chelation, the remaining NHcan be derivatized freely to improve the organ/tissueselectivity,6 fine tune the intramolecular energy transfer,7

or increase the enzymatic responding ability.8 Secondly, amaximum of two coordinated sites is left for the binding ofwater molecules in these heptadentate Ln3þ complexes,which makes the relaxivity of Gd3þ complexes increaseeffectively because the inner-sphere proton relaxivity islinearly proportional to the number of directly coordinatedwater molecules.9 Lastly, three chelating moieties withnegative charges such as carboxylate can neutralize theLn3þ; the resulting neutral complexes with low osmolalitycan effectively reduce the pain and tissue sloughing duringthe injection process.

Several selective functionalizations of cyclen to prepareDO3A derivatives have been reported. Before the alkylationis performed, three amines in the cyclen can be temporarilyprotected by the protective groups such as tert-butyloxy-carbonyl,10 tosyl11, formyl,12 trifluoroacetyl,13 or by thesterically hindered reagents including phosphoryl species,14

glyoxal aminal,15 and metal carbonyls M(CO)6 (M¼Cr, Mo,

0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2004.04.086

Tetrahedron 60 (2004) 5595–5601

Figure 1. Structures of DOTA, Gd-DOTA and DO3A derivatives.

q Supplementary data associated with this article can be found in the online version, at doi: 10.1016/j.tet.2004.04.086

Keywords: One-step synthesis; Alkylation; Cyclen.* Corresponding author. Tel.: þ852-2859-2157; fax: þ852-2547-2933; e-mail address: [email protected]

W)16 from the inside of the tetraazamacrocycles in astoichiometric ratio. Therefore, all the procedures aboveinvolve a protection, alkylation, deprotection, and alkyl-ation sequence. Even in the recent work of Welch, trisN-alkylated cyclens were prepared from cyclen through foursuch steps.17 In principle, the most efficient method toprepare tris N-alkylated cyclens is selective alkylation ofthree NH on the cycle with chelating agents (such as aceticacid, amides, etc.) directly, after which selected functionalgroups can be introduced to the remaining amine. Eventhough several synthetic procedures for tris N-alkylatedcyclens through one-step alkylation were reported,18

unfortunately they are not always general, and the yieldsof tris N-alkylated cyclens fluctuate between 20 and 50%due to the formation of tetra N-alkylated byproducts. Hence,the challenge still remains in exploiting a straightforwardprocedure to prepare tris N-alkylated cyclens with highselectivity.

2. Results and discussion

In our previous studies, we described direct methods for thepreparations of mono N-alkylated cyclen,19 and 1,4-bisN-alkylated cyclen.20 1,4-Bis(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane 1a as the only bis N-alkyl-ated isomer was isolated in good yield by the treatment of2.0 equiv. of tert-butyl bromoacetate with cyclen in chloro-form. As reported, 6–10% of tris (tert-butoxycarbonyl-methyl)-1,4,7,10-tetraazacyclododecane 1 was developedas a side-product in this circumstance.20 To promote theyield of this important precursor of DO3A chelate, anadditional electrophile was added under similar reactionconditions. The yield of 1 increased dramatically, and anoptimal value of 77% was achieved in the presence of3.5 equiv. of electrophile, much higher than that previouslyreported.18 Surprisingly, apart from about 20% of 1,4-bisN-alkylated product 1a, no other alkylated products wereisolated.

To clarify the solvent and auxiliary base’s effect on theregioselectivity, this reaction was also performed in

different solvents with various auxiliary bases (Table 1).The CHCl3/(Et)3N system afforded the most satisfactoryresult (entry 4, Table 1). The effect of solvents on the yieldand selectivity is obvious. Weakly polar and aproticsolvents like CH3Cl and CH2Cl2 are preferable to polar,aprotic solvents such as DMF, CH3CN, and polar, proticsolvents such as CH3OH, which lead to substantial losses inyield and selectivity22 (entries 6–8, Table 1). Auxiliarybases also play an important role in determining theregioselectivity (entries 1–4, Table 1). A yield of only35% of tris N-alkylated cyclen 1 was achieved if (Et)3N wasreplaced by K2CO3. Furthermore, in the presence of K2CO3,nearly all cyclen was tetra N-alkylated in the presence of8.0 equiv. of electrophile.

To further investigate the regioselectivity and distribution ofdifferent N-alkylated products in the CHCl3/(Et)3N system,a series of experiments was conducted in the presence oftert-butyl bromoacetate from 2.0 to 8.0 equiv. (Fig. 2). 1,4-Bis N-alkylated cyclen 1a and tris N-alkylated cyclen 1 werethe only two products that were isolated in the wholereaction process. The yield of 1 increased gradually andreached approximately 77% in the presence of about3.5 equiv. of alkylating agent. At the same time, the yieldof 1a decreased from 81 to 20%. Interestingly, theregioselectivity was kept nearly constant, and no tetraN-alkylated cyclen was found even in a large excess of8.0 equiv. of electrophile.

To demonstrate the generality of this protocol in theCHCl3/(Et)3N system, selected alkylating agents, especiallythose that have been widely used as chelating moieties2b–7b, were examined with cyclen, respectively (Table 2).As expected, corresponding tris N-alkylated cyclens 2–7and 1,4-bis N-alkylated cyclens 2a–7a were obtained withgood yields in the presence of 3.5 and 2.0 equiv. ofelectrophiles, respectively, with no detection of 1,7-bisand tetra N-alkylated cyclens at the same time.

Compounds 1 and 1a were crystallized from a mixture of9:1 acetone/H2O by slow evaporation. Interestingly, singlecrystal X-ray structures demonstrated that both 1 and 1awere in the form of their mono hydrochloride salts. In

Table 1. Effect of solvent and auxiliary base on the yield andregioselectivity

Entry Cond.a Base Yield (%)b

Tris Bis Tetra rc

1 CHCl3 Free 51 40 n.d.d .992 CHCl3 Pyridinee 63 28 n.d.d .993 CHCl3 K2CO3

f 35 32 27 .994 CHCl3 (Et)3Ne 77 20 n.d.d .995 CH2Cl2 (Et)3Ne 62 32 n.d.d .996 DMF (Et)3Ne 54 31 ,7 3.77 CH3CN (Et)3Ne 48 25 21 2.48 MeOH (Et)3Ne 42 31 22 2.8

a 3.5 equiv. tert-butyl bromoacetate, 14–20 h, 298 K.b Isolated yield of purified product.c Ratio of 1,4/1,7 bis-alkylated cyclen determined by 1H NMR and 13C

NMR.21

d Not detect.e 10.0 equiv. of (Et)3N or pyridine.f 5.0 equiv. of K2CO3.

Figure 2. Plot of yields of tris and 1,4-bis N-alkylated cyclens 1 (X) and 1a(W) as a function of the number of equivalents of tert-butyl bromoacetateadded (298 K, CHCl3/(Et)3N).

C. Li, W.-T. Wong / Tetrahedron 60 (2004) 5595–56015596

previous reports of the crystal structure of DO3A23 orDOTA derivatives24, the 12-membered cyclen rings usuallyadopted a square [3333] conformation (A, Fig. 5). However,the common feature of both 1 and 1a is that an unalkylatedN atom on the cyclen ring is protonated, and H-bonds withthe opposite N atom. This H-bonding results in the squaremacrocycle ring being ‘pressed’ to the rectangular [2424]conformations (B, Fig. 5). In the structure of 1·HCl25

(Fig. 3), hydrogen bonding interaction was found betweenN(1) and protonated N(3), with a bonding distance of3.032 A, and the N–H· · ·N angle was 150.28. We proposethat its protonation prevents N(3) on the cyclen from beingalkylated, even in the presence of a large excess ofelectrophiles. In the structure of 1a·HCl26 (Fig. 4),H-bonding developed between the unalkylated N(3) andopposite N(1), with a distance of 2.867 A, which was evenshorter than that in 1·HCl, and the N–H· · ·N angle was153.58. For the two neighboring unalkylated amines in 1a,N(3) was protonated and H-bonded with opposite N(1);

meanwhile, the nucleophilicity of N(4) decreased substan-tially due to its intraannular lone pair, which might explainwhy part of 1,4-bis N-alkylated products can not betransformed to the tris or tetra N-alkylated products evenin excess of electrophiles.

3. Conclusion

In conclusion, we developed a general one-step syntheticstrategy to prepare the tris N-alkylated cyclens in a yield ofup to 86%. This unique regioselectivity can be wellunderstood by the single crystal structures of 1 and 1a.Under the CHCl3/(Et)3N reaction condition, nitrogen atomsin the macrocycle can be selectively protonated, whichprevents its further alkylation even in a large excess ofelectrophile, and ultimately gives rise to this regio-selectivity. As far as we are aware, this is the first timethat the 12-membered cyclen ring has been observed to

Table 2. Yield and regioselectivity of selected electrophiles with cyclen in the condition of CHCl3/(Et)3N

Entry Electrophiles Product Yield (%)a

1 1b

1. R¼CH2COOBut Tris: 77b

1a. R¼H 1,4-Bis: 81c, r.99d

2 2b

2. R¼CH2Ph Tris: 86%b

2a. R¼H 1,4-Bis: 78c, r.99d

3 3b

3. R¼CH2CHvCH2 Tris: 76%b

3a. R¼H 1,4-Bis: 73c, r.99d

4 4b

4. R¼CH2CONHCH(Ph)2 Tris: 81b

4a. R¼H 1,4-Bis: 71c, r.99d

5 5b

5. R¼CH2CONHCp

HMePh Tris: 71b

5a. R¼H 1,4-Bis: 73c, r.99d

6 6b

6. R¼CH2CONH(CH2)5CH3 Tris: 84b

6a. R¼H 1,4-Bis: 75c, r.99d

7 7b

7. R¼CHMeCOOEt Tris: 65b

7a. R¼H 1,4-Bis: 70c

a Isolated yield of purified product.b In presence of 3.5 equiv. of halides.c In presence of 2.0 equiv. of halides.d Ratio of 1,4/1,7 N-alkylated cyclen.

C. Li, W.-T. Wong / Tetrahedron 60 (2004) 5595–5601 5597

change from square to rectangular conformations viaintraannular H-bonding (Fig. 5). The attractive features ofthis method such as high yield, operational convenience,cost and labor economy will provide more opportunities tocreate novel ligands based on tris N-alkylated cyclenderivatives, and thus facilitate the application of lanthanidecomplexes in drug discovery.

4. Experimental

4.1. General methods

All reactions were carried out under an argon atmosphereusing oven-dried glassware. CHCl3 and CH2Cl2 weredistilled from calcium hydride and stored over 4 A

Figure 4. X-ray crystal structure of 1a.

Figure 3. X-ray crystal structure of 1.


molecular sieves. Triethylamine were distilled from calciumhydride and stored over sodium hydroxide. Flash chroma-tography was performed on aluminum oxide 90 activeneutral (particle size 70–230 mesh) using CHCl3/CH3OH aseluting solvents. NMR spectra were measured in CDCl3 orCD3OD with SiMe4 as an internal standard at ambienttemperature on a Bruker Avance DPX 300 or 400 FourierTransform Spectrometer. Mass spectra were obtained at aFinnigan MAT 95 mass spectrometer for high resolutionFast Atom Bombardment (FAB) mass spectra, and at a LCQquadrupole ion trap mass spectrometer for low resolutionElectron Spray Ionization source (ESI) mass spectra.Elemental analyses were performed in the Department ofChemistry, City University of Hong Kong.

4.2. General method for tris-N alkylated-1,4,7,10-tetraazacyclododecane (1–7)

3.5 equiv. of appropriate electrophile (7.6 mmol) dissolvedin 10.0 mL of anhydrous chloroform was added dropwise toa mixture of 1,4,7,10-tetraazacyclododecane (cyclen)(400.0 mg, 2.32 mmol) and 10.0 equiv. triethylamine(2.3 g, 23.2 mmol) in 40 mL of anhydrous chloroformunder argon atmosphere. The reaction mixture was stirredfor a further 16–20 h. The resulting solution was washed bywater (3£40 mL), and the organic phase was dried byNa2SO4. The solvent was removed, and the crude productswere purified by column chromatography on Al2O3 to affordthe products 1–7.

4.2.1. Tris-(tert-butoxycarbonylmethyl)-1,4,7,10-tetra-azacyclododecane·HCl (1). 1 was prepared as a whitesolid (0.98 g, 1.79 mmol); yield 77% mp 178–180 8C. 1HNMR (400 MHz, CDCl3): d 3.34 (4H, s), 3.26 (2H, s), 3.05(4H, s), 2.89–2.85 (12H, m), 1.47 (27H, s); 13C NMR(100 MHz, CDCl3): d 170.5 (2£C), 169.6 (C), 81.6 (3£C),58.2 (3£CH2), 51.3 (2£CH2), 51.1 (2£CH2), 49.2 (2£CH2),47.5 (2£CH2), 28.2 (3£CH3), 28.1 (6£CH3); ESI-MS m/z515 (MþH)þ; HRFAB-MS calcd for C26H51N4O6 (MþH)þ

515.3809; found 515.3811. Anal. calcd for C26H51N4O6Cl:C, 56.66; H, 9.33; N, 10.17. Found: C, 56.41; H, 9.61; N,10.34.

4.2.2. Tris-(benzyl)-1,4,7,10-tetraazacyclododecane·HCl(2). 2 was prepared as a colorless oil (0.96 g, 2.00 mmol),yield 86% 1H NMR (400 MHz, CDCl3): d 7.38–7.30 (8H,m), 7.28–7.22 (2H, m), 7.21–7.13 (3H, m), 6.90 (2H, d,

J¼6.8 Hz), 3.65 (4H, s), 3.35 (2H, s), 2.83–2.57 (16H, br,m); 13C NMR (100 MHz, CDCl3): d 138.8 (2£C), 138.1 (C),129.6 (2£CH), 129.5 (4£CH), 128.2 (4£CH), 128.1(2£CH), 127.6 (2£CH), 127.0 (CH), 62.2 (2£CH2), 51.8(CH2), 51.2 (2£CH2), 50.8 (2£CH2), 50.2 (2£CH2), 48.2(2£CH2); ESI-MS m/z 443 (MþH)þ; HRFAB-MS calcd forC29H39N4 (MþH)þ 443.3175, found 443.3171. Anal. calcdfor C29H39N4Cl: C, 72.70; H, 8.20; N, 11.69. Found: C,72.56; H, 8.36; N, 11.42.

4.2.3. Tris-(allyl)-1,4,7,10-tetraazacyclododecane·HCl(3). 3 was prepared as a colorless oil (579 mg,1.76 mmol), yield 76% 1H NMR (400 MHz, CDCl3): d5.80–5.70 (3H, m), 5.14–5.06 (6H, m), 3.11 (6H, d,J¼6.4 Hz), 2.73–2.50 (16H, br, m); 13C NMR (100 MHz,CDCl3): d 134.7 (2£CH), 130.8 (CH), 119.8 (CH2), 118.6(2£CH2), 60.7 (2£CH2), 50.3 (2£CH2), 49.7 (2£CH2), 49.0(2£CH2), 48.7 (2£CH2), 47.9 (CH2); ESI-MS m/z 293(MþH)þ; HRFAB-MS calcd for C17H33N4 (MþH)þ,293.2705, found 293.2714. Anal. calcd for C17H33N4Cl:C, 62.08; H, 10.11; N, 17.03. Found: C, 62.16; H, 10.36; N,16.82.

4.2.4. Tris-[(diphenyl)methylcarbamoylmethyl]-1,4,7,10-tetraazacyclododecane·HCl (4). 4 was prepared as acolorless oil (1.65 g, 1.88 mmol), yield 81% 1H NMR(400 MHz, CDCl3): d 8.66–8.60 (2H, br), 7.85–7.82 (1H,br), 7.22–7.06 (30H, m), 6.18 (2H, d, J¼6.3 Hz), 5.97 (1H,d, J¼6.3 Hz), 3.27–3.17 (6H, m), 2.72–2.25 (16H, br, m);13C NMR (100 MHz, CDCl3): d 171.5 (2£C), 171.3 (C),141.8 (4£C), 141.7 (2£C), 129.1 (12£CH), 128.1 (12£CH),127.8 (6£CH), 59.7 (3£CH), 58.2 (3£CH2), 51.3 (2£CH2),51.1 (2£CH2), 49.2 (2£CH2), 47.5 (2£CH2); ESI-MS m/z842 (MþH)þ; HRFAB-MS calcd for C53H60N7O3

(MþH)þ, 842.4758, found 842.4776. Anal. calcd forC53H60N7O3Cl: C, 72.46; H, 6.88; N, 11.16. Found: C,72.25; H, 6.65; N, 11.12.

4.2.5. Tris-[(R)-1-(1-phenyl)ethylcarbamoylmethyl]-1,4,7,10-tetraazacyclododecane·HCl (5). 5 was preparedas a colorless oil (1.14 g, 1.65 mmol), yield 71% 1H NMR(400 MHz, CDCl3): d 8.51–8.45 (2H, br), 8.16–8.12 (1H,br), 7.39–7.04 (15H, m), 5.04–4.80 (3H, m), 3.28–3.03(6H, br, s), 2.73–2.22 (16H, br, m), 1.45 (9H, br, s); 13CNMR (100 MHz, CDCl3): d 171.0 (C), 170.8 (C), 170.6 (C),144.1 (C), 143.8 (2£C), 128.4 (6£CH), 127.1 (3£CH),126.4 (6£CH), 60.7 (2£CH2), 60.6 (CH2), 54.2 (2£CH2),53.2 (2£CH2), 52.1 (2£CH2), 48.9 (CH), 48.7 (2£CH), 46.7(2£CH2), 22.5 (CH3), 21.8 (2£CH3); ESI-MS m/z 656(MþH)þ; HRFAB-MS calcd for C38H54N7O3 (MþH)þ,656.4288, found 656.4284. Anal. calcd for C38H54N7O3-Cl·H2O: C, 64.25; H, 7.95; N, 13.80. Found: C, 64.44; H,7.79; N, 13.99.

4.2.6. Tris-(hexylcarbamoylmethyl)-1,4,7,10-tetraaza-cyclododecane·HCl (6). 6 was prepared as a colorless oil(1.23 g, 1.95 mmol), yield 84% 1H NMR (400 MHz,CDCl3): d 7.95–7.72 (3H, br, m), 3.14–3.10 (12H, br, s),2.75–2.63 (8H, br, m), 2.60–2.46 (8H, br, m), 1.43–1.41(6H, br, m), 1.23–1.10 (18H, br, s), 0.77 (9H, br, s); 13CNMR (100 MHz, CDCl3): d 171.2 (C), 170.9 (2£C), 60.7(3£CH2), 56.2 (CH2), 55.1 (CH2), 53.2 (2£CH2), 52.6(2£CH2), 47.1 (2£CH2), 39.5 (CH2), 39.4 (2£CH2), 31.4

Figure 5. Conformations of 12-membered cyclen ring.


(2£CH2), 31.3 (CH2), 29.5 (2£CH2), 29.4 (CH2), 26.6(2£CH2), 26.4 (CH2), 22.4 (3£CH2), 13.8 (3£CH3); ESI-MS m/z 596 (MþH)þ; HRFAB-MS calcd for C32H66N7O3


4.2.7. Tris-[ethyloxycarbonyl-1-methylmethyl]-1,4,7,10-tetraazacyclododecane·HCl (7) (racemic mixture). 7 wasprepared as a colorless oil (0.71 g, 1.51 mmol), yield 65%.1H NMR (400 MHz, CDCl3): d 4.04 (6H, br, s), 3.54–3.50(1H, m), 3.36–3.32 (2H, m), 3.03–2.36 (16H, br, m), 1.28–1.06 (18H, m); ESI-MS m/z 473 (MþH)þ; HRFAB-MScalcd for C23H45N4O6 (MþH)þ, 473.3339, found 473.3336.Anal. calcd for C23H45N4O6Cl·H2O: C, 52.41; H, 8.99; N,10.63. Found: C, 52.15; H, 8.79; N, 10.47.

4.3. General method for 1,4-bis N-alkylated-1,4,7,10-tetraazacyclododecane 1a–7a

2.0 equiv. of appropriate electrophiles (4.64 mmol) dis-solved in 10.0 mL anhydrous chloroform was addeddropwise to a mixture of 1.0 equiv. 1,4,7,10-tetraazacyclo-dodecane (cyclen) (400.0 mg, 2.32 mmol) and 10.0 equiv.triethylamine (2.32 g, 23.20 mmol) in 40 mL anhydrouschloroform under a N2 atmosphere for approximately halfan hour. The reaction mixture was allowed to continuouslystir for a further 12–14 h. The resulting solution waswashed by water (3£40 mL) then the organic phase wasdried by Na2SO4. The solvent was removed, and the crudeproducts were purified by column chromatography onAl2O3 to afford the products 1a–7a.

4.3.1. 1,4-Bis (tert-butoxycarbonylmethyl)-1,4,7,10-tetra-azacyclododecane·HCl (1a). 1a was prepared as a whitepower solid (821 mg, 1.88 mmol); yield 81% 1H NMR(400 MHz, CDCl3): d 3.32 (4H, s), 2.98–2.96 (8H, m),2.89–2.87 (8H, m), 1.41 (18H, s); 13C NMR (100 MHz,CDCl3): d 170.1 (C), 81.6 (2£C), 53.4 (2£CH2), 51.1(2£CH2), 49.9 (2£CH2), 46.5 (2£CH2), 46.1 (2£CH2), 28.2(6£CH3); IR (KBr, cm21) 2976, 1732, 1715, 1636, 1559,1457, 1167; ESI-MS m/z 401 (MþH)þ; HRFAB-MS calcdfor C20H41N4O4 (MþH)þ, 401.3128, found 401.3130. Anal.calcd for C20H41N4O4Cl: C, 54.97; H, 9.46; N, 12.82.Found: C, 55.07; H, 9.76; N, 12.57.

4.3.2. 1,4-Bis (benzyl)-1,4,7,10-tetraazacyclodode-cane·HCl (2a). 2a was prepared as a colourless oil(704 mg, 1.81 mmol); yield 78%. 1H NMR (400 MHz,CDCl3): d 7.28–7.16 (10H, m), 3.51 (4H, s), 2.85 (4H, br,s), 2.80–2.74 (4H, m), 2.67–2.61 (4H, m), 2.57 (4H, br, s);13C NMR (100 MHz, CDCl3): d 138.0 (2£C), 129.9(4£CH), 128.8 (4£CH), 127.6 (2£CH), 57.6 (2£CH2),51.5 (2£CH2), 51.2 (2£CH2), 47.1 (2£CH2), 46.2 (2£CH3);ESI-MS m/z 353 (MþH)þ; HRFAB-MS calcd for C22H33N4

(MþH)þ, 353.2705, found 353.2711. Anal. calcd forC22H33N4Cl: C, 67.93; H, 8.55; N, 14.40. Found: C,67.66; H, 8.51; N, 14.71.

4.3.3. 1,4-Bis (allyl)-1,4,7,10-tetraazacyclododecane·HCl(3a). 3a was prepared as a white power solid (488 mg,1.69 mmol); yield 73%. 1H NMR (400 MHz, CDCl3): d5.62–5.51 (2H, m), 4.92–4.86 (4H, m), 2.89–2.87 (4H, d,

J¼6.4 Hz), 2.62 (4H, br, s), 2.52–2.47 (4H, m), 2.38–2.35(4H, m), 2.31 (4H, br, s); 13C NMR (100 MHz, CDCl3): d133.9 (2£CH), 118.1 (2£CH2), 55.4 (2£CH2), 50.5(2£CH2), 50.0 (2£CH2), 46.6 (2£CH2), 45.5 (2£CH2);ESI-MS m/z 253 (MþH)þ; HRFAB-MS calcd for C14H29N4

(MþH)þ, 253.2392, found 253.2384. Anal. calcd forC14H29N4Cl: C, 58.21; H, 10.12; N, 19.40. Found: C,58.41; H, 9.89; N, 19.22.

4.3.4. 1,4-Bis-[(diphenyl)methylcarbamoylmethyl]-1,4,7,10-tetraazacyclododecane·HCl (4a). 4a was pre-pared as a colorless oil (1.13 g, 1.65 mmol); yield 71% 1HNMR (400 MHz, CDCl3): d 7.25–7.07 (20H, m), 6.21 (2H,m), 3.19 (4H, s), 2.64–2.17 (16H, m); 13C NMR (100 MHz,CDCl3): d 171.3 (2£C), 142.1 (4£C), 128.9 (8£CH), 128.1(4£CH), 127.7 (8£CH), 59.4 (2£CH2), 52.5 (2£CH2), 51.3(2£CH2), 50.3 (2£CH), 48.5 (2£CH2), 47.5 (2£CH2); ESI-MS m/z 647 (MþH)þ; HRFAB-MS calcd for C38H47N8O2


4.3.5. 1,4-Bis-[(R)-1-(1-phenyl)ethylcarbamoylmethyl]-1,4,7,10-tetraazacyclododecane·HCl (5a). 5a was pre-pared as a colorless oil (898 mg, 1.69 mmol); yield 73%1H NMR (400 MHz, CD3OD): d 7.37–7.10 (10H, m),5.04–4.92 (2H, m), 3.26–3.07 (4H, q, J¼8.2, 6.3 Hz),2.75–2.60 (16H, m), 1.52 (6H, d, J¼7.0 Hz); 13C NMR(100 MHz, CD3OD): d 171.6 (2£C), 143.8 (2£C), 128.6(4£CH), 127.0 (2£CH), 126.1 (4£CH), 57.3 (2£CH2), 52.7(2£CH2), 48.6 (2£CH2), 48.0 (2£CH), 45.7 (2£CH2), 44.9(2£CH2), 21.1 (2£CH3); ESI-MS m/z 495 (MþH)þ;HRFAB-MS calcd for C28H43N6O2 (MþH)þ, 495.3447,found 495.3451. Anal. calcd for C28H43N6O2Cl: C, 63.32;H, 8.16; N, 15.82. Found: C, 63.57; H, 8.27; N, 15.77.

4.3.6. 1,4-Bis-[(hexylcarbamoylmethyl)-1,4,7,10-tetra-azacyclododecane·HCl (6a). 6a was prepared as a colorlessoil (886 mg, 1.74 mmol); yield 75% 1H NMR (400 MHz,CDCl3): d 3.32 (4H, s), 3.22–3.11 (4H, br, m), 2.85–2.70(8H, m), 2.63–2.47 (8H, m), 1.61–1.47 (4H, br, s), 1.40–1.27 (12H, br, s), 0.88 (6H, br, s); 13C NMR (100 MHz,CDCl3): d 173.2 (C), 172.2 (C), 57.5 (CH2), 56.3 (CH2),52.5 (2£CH2), 52.0 (2£CH2), 45.3 (2£CH2), 44.3 (2£CH2),39.2 (CH2), 39.0 (CH2), 31.2 (CH2), 31.1 (CH2), 29.1 (CH2),28.9 (CH2), 26.3 (CH2), 26.1 (CH2), 22.2 (2£CH2), 13.0(CH2), 12.9(CH2); ESI-MS m/z 455 (MþH)þ; HRFAB-MScalcd for C24H51N6O2 (MþH)þ, 455.4074, found 455.4065.Anal. calcd for C24H51N6O2Cl·H2O: C, 56.61; H, 10.49; N,16.51. Found: C, 56.38; H, 10.42; N, 16.33.

4.3.7. 1,4-Bis-(ethyloxycarbonyl-1-methylmethyl)-1,4,7,10-tetraazacyclododecane·HCl (7a) (racemicmixture). 7a was prepared as a colorless oil (677 mg,1.62 mmol); yield 70% 1H NMR (400 MHz, CDCl3): d 4.01(4H, br, s), 3.43–3.40 (2H, m), 3.03–2.36 (16H, br, m),1.28–1.06 (12H, m); ESI-MS m/z 373.3 (MþH)þ; HRFAB-MS calcd for C18H37N4O4 (MþH)þ, 373.2815, found373.2825. Anal. calcd for C18H37N4O4Cl·0.5 H2O: C,51.73; H, 9.16; N, 13.40. Found: C, 51.59; H, 9.33 N, 13.12.

4.3.8. X-ray crystallography. Data collections wereperformed at 20 8C with a Bruker AXS SMART 1000


CCD diffractometer that was interfaced with a SiliconGraphics INDYe workstation using the program packageTeXsan from MSC (version 1.7–2.0). The structures weresolved by direct methods (SIR92 or ORIENT), and refinedby full-matrix least-squares methods on F (teXsan).Crystallographic data for compound 1 and 1a have beendeposited with the Cambridge Crystallographic Data Centre(Deposition numbers CCDC 206158 and 206159). Copies ofthe data can be obtained free of charge on application toCCDC, 12 Union Road, Cambridge CB2 1EZ, UK (email:[email protected]).

Acknowledgements

We gratefully acknowledge financial support from the HongKong Research Grants Council and the University of HongKong. This work was also supported by the Area ofExcellence Scheme of the University Grants Committee(Hong Kong).

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25. Crystal data for 1·HCl: C26H52ClN4O6.50, M¼561.18, mono-

clinic, space group P2/c (#13), a¼22.076(4), b¼6.699(1),

c¼23.700(4) A, b¼111.55(1)8, V¼3259.9(9) A3, Z¼4,

Dcalc.¼1.143 g/cm3, m(Mo Ka)¼0.159 cm21, T¼298 K,

20143 reflections collected, 7922 unique (Rint¼0.023).

Refinement on F, final R1¼0.0459 (for 4274 reflections with

I$2.00s (I)), wR2¼0.0562.

26. Crystal data for 1a·HCl: C40H88Cl2N8O11, M¼928.09,

tetragonal, space group P4 (#81), a¼28.798(3), b¼28.798

(3), c¼6.407(1) A, V¼5313.5(10) A3, Z¼4, Dcalc¼1.160

g/cm3, m (Mo Ka)¼0.179 cm21, T¼298 K, 33108 reflections

collected, 6576 unique (Rint¼0.051). Refinement on F, final

R1¼0.0735 (for 3768 reflections with I$2.00s (I)),

wR2¼0.1081 (for 3768 reflections).


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a selective one-step synthesis of tris n-alkylated cyclens

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