Efficient preparation of 1,4,8-trimethylcyclam and its conversion into a thioalkyl-pendant pentadentate chelate

Article abstract of DOI:10.1039/b311520h

A facile synthesis of 1,4,8-trimethylcyclam and a thioalkyl-pendant derivative are reported, and the X-ray crystal structure of a nickel(II) complex illustrates structural consequences of appending the thiolate donor onto the macrocycle.

Full text of DOI:10.1039/b311520h

Efficient preparation of 1,4,8-trimethylcyclam and its conversion into a
thioalkyl-pendant pentadentate chelate
Jason A. Halfen*a and Victor G. Young, Jr.b
a Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, WI 54702, USA.
E-mail: halfenja@uwec.edu; Fax: 715-836-4979; Tel: 715-836-4360
b Department of Chemistry, University of Minnesota, 207 Pleasant St. S.E., Minneapolis, MN 55455, USA.
E-mail: young@chem.umn.edu; Fax: 612-626-7541; Tel: 612-625-6897
Received (in West Lafayete, IN, USA) 19th September 2003, Accepted 3rd October 2003
First published as an Advance Article on the web 22nd October 2003
A facile synthesis of 1,4,8-trimethylcyclam and a thioalkyl-
pendant derivative are reported, and the X-ray crystal
structure of a nickel(II) complex illustrates structural
consequences of appending the thiolate donor onto the
macrocycle.
clam)nickel(II) complex, although the yield of 1 is moderate and
the reaction conditions are hazardous, as significant amounts of
cyanide are required for demetallation of the macrocyclic
product.7 An alternate route to 1 involving cyclization of
selectively N-methylated precursors has also been described,
although chromatographic purification of several species is
required to obtain pure product.8 The utility of 1 is illustrated by
its conversion into pentadentate chelate 2, which contains a
pendant thioalkyl group. The X-ray crystal structure of a
mononuclear Ni(II) complex (3) of pentadentate 2 is also
reported, illustrating structural perturbations caused by attach-
ing the thiolate donor to the macrocyclic ligand.
Tetraazamacrocycles such as 1,4,8,11-tetraazacyclotetradecane
(cyclam) have a long history in synthetic inorganic chemistry
and a burgeoning significance in medicinal chemistry.1,2
Selective derivatization of the secondary amines in cyclam is a
key step in the development of new ligands for transition metals
and new bioactive agents alike.3 Statistical methods using large
excesses of cyclam in conjunction with yield-limiting quantities
of electrophiles have been used to mono-alkylate cyclam,
although the use of expensive, excess macrocycle renders these
methods unattractive for large-scale use.4 Selective protection
methods have been used to generate cyclam macrocycles
possessing less than four BOC or tosyl protecting groups;
however, yields are often modest and pure macrocycles are
usually isolated only after chromatographic purification.5
Recent synthetic advances, taking advantage of the reactivity of
cyclic bisaminal derivatives, have provided access to ster-
eochemically well-defined difunctionalized cyclams.6 How-
ever, facile routes to trialkylcyclams, which could serve as
precursors to new pentadentate ligands or bioactive agents, have
yet to be described. Herein we report an efficient, rapid
synthesis of 1,4,8-trimethylcyclam (1, Scheme 1) that proceeds
in excellent overall yield and, of equal significance, completely
avoids tedious chromatographic purifications of synthetic
intermediates. 1,4,8-Trimethylcyclam (1) has been prepared
previously by rigorous methylation of a (1,8-dimethylcy-
The synthesis of 1 begins with 1,4,8-tris(trifluoroacetyl)cy-
clam, the preparation of which from cyclam and ethyl
trifluoroacetate (EtOTFA) was described recently.9 Tosylation
of this triamide (TsCl, Et3N, CH2Cl2, D) provides 1-(p-
toluenesulfonyl)-4,8,11-tris(trifluoroacetyl)-cyclam as a tan
solid. Characterization of this material by 1H NMR is
complicated by the hindered rotation of the three trifluor-
oacetamide groups. However, these groups are readily hydro-
lyzed (KOH, CH3OH, D), affording 1-(p-toluenesulfonyl)-
cyclam as an oil, which exhibits the expected set of NMR
spectroscopic features. Specifically, the 1H NMR spectra of this
species and subsequent C1-symmetric cyclams exhibit two high
field quintets, arising from the middle –CH2– groups of the two
propylene linkages in the cyclam macrocyclic ring. Permethyla-
tion of 1-(p-toluenesulfonyl)-cyclam (H2CO, HCO2H, D)
followed by detosylation (HBr/HOAc, C6H5OH, D) provides
the hydrobromide salt of 1,4,8-trimethylcyclam (1) as a white
solid, from which the free base macrocycle can be readily
liberated using a basic aqueous workup. Thus, the overall yield
of 1 from commercially available cyclam is 60%, and can be
rapidly accessed on a preparative scale without the need for
chromatographic purification at any point in its synthesis.†
1,4,8-Trimethylcyclam is a valuable precursor for the
preparation of chelates of potential utility in synthetic inorganic
and medicinal chemistry investigations. For example, reaction
of 1 with excess thirane (C6H6, D) affords thioethyl-pendant
ligand 2 (Scheme 1). This ligand has been described previously,
albeit in modest yield and with little exploration of its
coordination chemistry.10 To confirm the structure and compo-
sition of 2, its complex with Ni(II) was prepared by deprotona-
tion of the ligand (NaH, THF), followed by reaction with
hydrated Ni(ClO4)2. The green crystalline material thus ob-
tained, 3, was subjected to crystallographic characterization.
The X-ray crystal structure of 3 (Fig. 1) confirms the presence
of pentadentate chelate 2, which encapsulates a central Ni(II
)
ion.‡ The geometry of the metal is best described as distorted
square-pyramidal (t = 0.43)11 in which the Ni(II) ion is
displaced from the mean plane of the four amines toward the
pendant thiolate ligand by 0.38 Å. Relevant to the structure of 3
is that of a pentacoordinate Ni(II)-cyclam complex in which the
macrocyclic ligand bears two pendant thioether donors.12
Predictably, the axial Ni–S distance in that complex, 2.393 Å, is
longer than the Ni–S distance in 3, a difference that is rooted in
the divergent nature of their sulfur ligands (thioether vs.
thiolate). The structure of 3 is also related to that of
Scheme 1
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This journal is © The Royal Society of Chemistry 2003

2H), 1.66 (quint, 2H) ppm. 1-Tosyl-4,8,11-trimethylcyclam (2.32 g, 6.00
mmol) and phenol (1.34 g, 14.2 mmol) were combined in 33% HBr/HOAc
(60 ml) and heated to 100 °C for 16 h. The mixture was filtered, the solid
washed with Me2CO and Et2O and then dissolved in aqueous KOH to
liberate the free macrocyclic base. The mixture was extracted with CH2Cl2,
and the extracts dried and evaporated to provide 1,4,8-trimethylcyclam, 1,
as a colorless oil (1.10 g, 76%). 1H NMR d 2.66 (t, 2H), 2.61 (t, 2H), 2.44
(t, 2H), 2.39 (m, 6H), 2.35 (t, 2H), 2.14 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H),
1.68 (quint, 2H), 1.56 (quint, 2H) ppm.
‡ X-ray crystallographic data for 3: C15H33ClN4NiO4S, M = 459.67,
monoclinic, a = 8.3748(15), b = 14.505(3), c = 8.9820(16) Å, b =
113.659(3)°, V = 999.4(3) Å3, T = 173 K, space group P21, Z = 2, m(Mo
Ka) = 1.237 mm21, 11765 reflections collected, 4729 unique (Rint
=
0.0550) which were used in all calculations. The specimen was a non-
merohedral twin with the twin law (by rows) [20.03015, 0.00732, 0.91909/
0.04477, 20.99794, 0.03830/ 1.08327, 0.01048, 0.02948], which corre-
sponds to a 180 degree rotation about direct axis [1.00, 0.01, 0.95].14 The
reflections were integrated for both twin components with SAINT
V6.35A.15 Absorption correction was performed with TWINABS V1.05.16
Redundant reflections were removed with STRIP-REDUNDANT.17 248
reflections were common to both twin components. Least-squares refine-
ments were performed with SHELXL V6.10.18 The final residuals for all
data were R1 = 0.0433 and wR2 = 0.0728. CCDC 220192. See http://
www.rsc.org/suppdata/cc/b3/b311520h/ for crystallographic data in .cif or
other electronic format.
Fig. 1 Thermal ellipsoid representation (50% probability boundaries) of the
cationic portion of the X-ray crystal structure of 3 with hydrogen atoms
omitted for clarity. Significant interatomic distances (Å) and angles (°)
include: Ni–N1, 2.117(2); Ni–N2, 2.148(3); Ni–N3, 2.129(3); Ni–N4,
2.166(3); Ni–S1, 2.2785(9); N1–Ni–N3, 172.59(10); N1–Ni–N2, 93.46(9);
N3–Ni–N2, 84.91(9); N1–Ni–N4, 84.66(10); N3–Ni–N4, 92.76(9); N2–Ni–
N4, 146.94(10); N1–Ni–S1, 88.48(7); N3–Ni–S1, 98.91(7); N2–Ni–S1,
106.83(7); N4–Ni–S1, 106.11(7).
1 J. Reedijk, in Comprehensive Coordination Chemistry, Vol. 2. G.
Wilkinson, Ed.; Pergamon Press, Oxford, 1987; L. F. Lindroy, in The
Chemistry of Macrocyclic Ligand Complexes; Cambridge University
Press: Cambridge, 1989.
2 R. B. Lauffer, Chem. Rev., 1987, 87, 901. For a recent reference, see: G.
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3 F. Denat, S. Brandès and R. Guilard, Synlett, 2000, 561.
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5 For three BOC or Ts protecting groups, see: D. D. Dischino, E. J.
Delaney, J. E. Emswiler, G. T. Gaughan, J. S. Prasad, S. K. Srivastava
and M. F. Tweedle, Inorg. Chem., 1991, 30, 1265; S. Brandès, C. Gros,
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65.
6 R. Tripier, J.-M. Lagrange, E. Espinosa, F. Denat and R. Guilard, Chem.
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[(Me4cyclam)Ni(SPh)]PF6 (4) in which a distorted square
pyramidal Ni(II) ion is bound by a tetramethylcyclam ligand and
an axial benzenethiolate donor.13 The Ni–S distance in 4 (2.347
Å) is longer than that found in 3, and the pentacoordinate Ni(II
)
ion in 4 exhibits a smaller trigonal distortion (t = 0.25).11 Both
of these geometric differences are ascribed to the thiolate donor
being covalently tethered to the macrocyclic ligand in 3, a
condition that is absent in 4.
Compounds 1 and 2 are two examples of selectively alkylated
cyclams that can be prepared using the general methodology
described herein. The structural differences between 3 and 4
suggest that pentadentate ligands derived from 1,4,8-trime-
thylcyclam may provide access to metal complex structures or
reactions that are inaccessible without covalent attachment of
the fifth donor to the macrocyclic ring.
This work was supported by the National Science Foundation
(Grant CHE-0243951), the Camille and Henry Dreyfus Founda-
tion (Henry Dreyfus Teacher-Scholar Award), the University of
Minnesota/NSF RSEC program (Grant CHE-0113894), and the
University of Wisconsin-Eau Claire.
9 W. Yang, C. M. Giandomenico, M. Sartori and D. A. Moore,
Tetrahedron Lett., 2003, 44, 2481.
Notes and references
† Synthesis of 1: 1,4,8-tris(trifluoroacetyl)cyclam (2.51 g, 5.23 mmol), p-
toluenesulfonyl chloride (1.25 g, 6.56 mmol) and Et3N (0.80 ml, 5.8 mmol)
were combined in CH2Cl2 (30 ml) and refluxed 18 h. The mixture was
evaporated, the residue partitioned between H2O and CH2Cl2, the organic
phase separated, dried and evaporated to provide 1-tosyl-4,8,11-tris(tri-
fluoroacetyl)-cyclam (3.34 g, 99%). This material and KOH (1.24 g, 22.1
mmol) were combined in CH3OH (30 ml) and refluxed for 1.5 h. The
mixture was evaporated, the residue partitioned between aq. NaOH and
CH2Cl2, the organic phase separated, dried and evaporated to provide
1-tosylcyclam (1.72 g, 96%). 1H NMR (400 MHz, CDCl3) d 7.60 (d, 2H),
7.24 (d, 2H), 3.16 (t, 2H) 3.11 (t, 2H), 2.78 (t, 2H), 2.69 (m, 10H), 2.36 (s,
3H), 1.72 (quint, 2H), 1.65 (quint, 2H) ppm. 1-Tosylcyclam (2.35 g, 6.82
mmol), HCO2H (90%, 10 ml) and HCHO (37%, 8 ml) were refluxed for 4
h. The solution was cooled and made basic by addition of KOH. The
mixture was extracted with CH2Cl2, the extracts dried and evaporated to
provide 1-tosyl-4,8,11-trimethylcyclam (2.32 g, 88%). 1H NMR d 7.65 (d,
2H), 7.27 (d, 2H), 3.20 (dt, 4H), 2.70 (m, 6H), 2.60 (t, 2H), 2.49 (t, 2H), 2.41
(m, 2H), 2.39 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H), 1.84 (quint,
10 D. Tschudin, A. Basak and T. A. Kaden, Helv. Chim. Acta, 1988, 71,
100.
11 A. W. Addison, T. N. Rao, J. Reedjik, J. van Rijn and G. C. Verschoor,
J. Chem. Soc., Dalton Trans., 1984, 1349.
12 C. L. Schmid, M. Neuburger, M. Zehnder, T. A. Kaden, K. Bujno and
R. Bilewicz, Helv. Chim. Acta, 1997, 80, 241.
13 M. S. Ram, C. G. Riordan, R. Ostrander and A. L. Rheingold, Inorg.
Chem., 1995, 34, 5884.
14 GEMINI, Bruker Analytical X-Ray Systems, Madison, WI, (2000).
15 SAINT V6.35A, Bruker Analytical X-Ray Systems, Madison, WI,
(2002).
16 TWINABS V1.05, (a) G. Sheldrick, 2003; (b) R. Blessing, Acta Cryst.,
1995, A51, 33.
17 W. W. Brennessel and V. G. Young, Jr., STRIP-REDUNDANT V1.2, A
program to remove duplicated reflections from HKLF 5 files, un-
published work (2002).
18 SHELXTL V6.10, Bruker Analytical X-Ray Systems, Madison, WI,
(2000).
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