Synthesis and characterization of 1,8-dithia-4,11-diazacyclotetradecane

Article abstract of DOI:10.1016/j.tetlet.2012.09.088

The synthesis of 1,8-dithia-4,11-diazacyclotetradecane L₃, a member of a series of [14]aneN₂S₂ ligands, has been synthesized and characterized. The crystal structures of [1,8-dithia-4,11- diazacylotetradecane] L₃

Full text of DOI:10.1016/j.tetlet.2012.09.088

Tetrahedron Letters 53 (2012) 6548–6551
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and characterization of 1,8-dithia-4,11-diazacyclotetradecane
Tia L. Walker, Wilhelm Malasi, Swaranjali Bhide, Thomas Parker, Dan Zhang, Abegel Freedman à,
Jody M. Modarelli à, James T. Engle §, Christopher J. Ziegler §, Paul Custer , Wiley J. Youngs ,
⇑
Michael J. Taschner
Department of Chemistry, The University of Akron, Akron, OH 44325, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2012
Revised 19 September 2012
Accepted 21 September 2012
Available online 28 September 2012
The synthesis of 1,8-dithia-4,11-diazacyclotetradecane L3, a member of a series of [14]aneN2S2 ligands,
has been synthesized and characterized. The crystal structures of [1,8-dithia-4,11-diazacylotetradecane]
L3 and [1,8-dithia-4,11-diazayclotetradecane dihydrochloride] L3Á2HCl are presented.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Thia aza macrocycle
Blue copper protein
N–S donor
Crystal structure
1,8-Dithia-4,11-diazacyclotetradecane
Following the structural characterization and analysis of Blue
Copper Proteins1, macrocyclic ligands have attracted much interest
as simple models for naturally occurring metal-macrocycle
centers.2 Several macrocyclic systems such as polythiaethers,3
polyazacycloalkanes,4 thia-aza,5 and trithiaethers6 have been syn-
thesized and investigated as synthetic analogs to date.7 These
ligands are also attractive for their enhanced stability with metal
ions when compared to the acyclic versions. The enhanced stabil-
ity, termed the ‘macrocyclic effect’ is in large part due to the donor
ligands being fixed in their orientation when compared to the acy-
clic counterparts, which have higher degrees of freedom.8–10
These ligands have not only been investigated as analogs for
metal protein interactions, but they have also been examined in
medicinal chemistry as anti-parasitic drugs, in biomedical applica-
tions, such as MRI contrast-enhancing agents and as therapeutic
agents in chelate therapy for metal intoxication, and ionophores.11
As reported by Siegfried and Kaden, the ideal N2S2 ligand has a
ring size of 14 with an alternating 2,3,2,3 arrangement of connect-
ing atoms for the complexation of Cu2+ which allows for minimal
structural distortion.12
L2, and 1,8-dithia-4,11-diazacyclotetradecane L3, are shown in
Figure 1. All three ligands have been mentioned throughout litera-
ture; however, only the synthesis of L1 has been reported to date.12
The synthesis of a di-benzo 14-membered macrocycle related to L3
was reported by Wild, which employed the reduction of a di-benzo
trans Schiff base precursor.13 However, the synthesis and charac-
terization of the parent ligand 1,8-dithia-4,11-diazacyclotetrade-
cane have not been reported to date. This is likely due to the
alternating arrangement of the thia-aza donor atoms rendering
the simple capping/condensation methods that are currently in
place for making thia, aza, and oxa crowns inappropriate due to
potential isomer formation.14
Reported here is the synthesis of 1,8-dithia-4,11-diazacyclote-
tradecane L3 via a convergent approach depicted in Scheme 1.
The primary amino groups of the starting material, cystamine
dihydrochloride 1 were protected with p-toluenesulfonyl chloride
in 90% yield.15 The tosylamide was chosen not only for its stability
but to also aid in the cyclization through its electronic effect. The
The three possible N–S mixed donor ligands 1,4-dithia-8,11-
diazacyclotetradecane L1, 1,11-dithia-4,8-diazacyclotetradecane
⇑
Corresponding author. Tel.: +1 330 972 6068; fax: +1 330 972 6085.
E-mail addresses: modarellijm@hiram.edu (J.M. Modarelli), Ziegler@uakron.edu
(C.J. Ziegler), youngs@uakron.edu (W.J. Youngs), mjt1@uakron.edu (M.J. Taschner).
Information regarding crystallography on compound L3.
à
Mass spectrometry.
Information regarding crystallography on compound L3Á2HCl.
§
Figure 1. 14-membered mixed N-S donor types.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.088

T. L. Walker et al. / Tetrahedron Letters 53 (2012) 6548–6551
6549
Scheme 1. Synthesis of 1,8-dithia-4,11-diazacyclotetradecane.
tosyl group makes it possible to deprotonate the tosylamide thus
creating a good nucleophile for the macrocyclization. Cleavage of
the disulfide bond using triphenylphosphine resulted in the forma-
tion of the intermediate thiol in situ.16,17 The thiol was converted
into the thiolate with aqueous NaOH and alkylated with 3-
chloro-1-aminopropane to afford 2 in 95% yield.
The second intermediate 2-[(3-chloropropyl)sulfanyl]acetyl
chloride 4 was synthesized by radical addition of mercaptoacetic
acid 3 to allyl chloride in the presence of a catalytic amount of
azobisisobutyronitrile (AIBN) to give the acid which was directly
converted into the acid chloride using thionyl chloride. Purification
by vacuum distillation produced 4 in 87%.18
Amine 2 undergoes acylation in CH2Cl2 with triethylamine, a
catalytic amount of 4-dimethylaminopyridine (DMAP), and acid
chloride 4 to produce the uncyclized amide 5 as a yellow oil, iso-
lated in 91% yield after chromatography.19 The intramolecular
cyclization was performed by adopting a modified Kellogg’s proce-
dure,20 to achieve relatively dilute conditions with slow addition
times. Either K2CO3 or Cs2CO3 can be employed as the base in
DMF at 100 °C. The resulting amide macrocycle is purified by
recrystallization in 58% yield.
Reduction of the tosylamide was accomplished using 2 equiv of
borane dimethyl sulfide in refluxing toluene.21 Following the
reduction, triethanolamine in methanol was added and the
reaction then refluxed for an additional 48 h to decompose
the amine-borane complex. Purification by column chromatogra-
phy yielded 85% of the tosylamine. Detosylation was carried out
using 33% HBr in acetic acid in the presence of phenol to give the
desired free amine L3 after basic workup.22 The amine was recrys-
tallized from ethyl acetate in 87% yield producing a tan solid.
Crystals of L3 suitable for X-ray diffraction were grown from
ethyl acetate. The crystal structure of L3 is shown in Figure 2. Com-
pound L3 crystallizes in the triclinic space group P-1 and adopts a
[3434] conformation according to Dale’s notation.23 The ring
adopts a rectangular endodentate conformation with carbon atoms
at the corners instead of the heteroatoms. The nitrogen atoms in
the ring are located in the center of the 4-atom connecting chains
with their hydrogens pointing toward the ring cavity. The crystal
structure of cyclam, reported by Raston, shows similar hydrogen
orientations for the nitrogens at the 4,11 positions with the excep-
tion that it also contains intramolecular hydrogen bonding interac-
tions.24 The N–N bond distance between the 4,11 positions through
the cavity is ꢀ4.69 Å and the S–S is ꢀ5.25 Å. The S–N at the 1,4
positions is ꢀ3.13 Å and the S–N at the 4,8 positions is ꢀ3.86 Å.
To further examine the structural characteristics of the ring, the
amine hydrochloride salt L3Á2HCl was synthesized. The amine
hydrochloride salt precipitated out as fine white crystals from a
50/50 mixture of ethanol/water. The crystal structure of L3Á2HCl
is also shown in Figure 2. The crystal system is monoclinic with
a space group of P2(1)/n and contains one molecule in the
asymmetric unit. The di-protonated form of the macrocycle adopts
an exodentate conformation with the heteroatoms located at the
Figure 2. The structures of 6 from EtOAc and 6Á2HCl from ethanol:water with 35% thermal ellipsoids. Hydrogen atoms with the exception of N–H positions have been omitted
for clarity.

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T. L. Walker et al. / Tetrahedron Letters 53 (2012) 6548–6551
Table 1
Dr. Jody Modarelli for her work on mass spectrometry funded by
grant NSF:MRI 1039259
Crystal data and structure refinement for L3 and L3Á2HCl
Identification code
L3
L3Á2HCl
Supplementary data
Empirical formula
Formula weight
Crystal System
Space group
Unit cell dimensions
C10 H22 N2 S2
234.42
Triclinic
C10 H26 Cl2 N2 O S2
325.35
Monoclinic
P2(1)/n
7.6164(6) Å
13.3949(11) Å
15.6467(13) Å
90°
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.
088.
P-1
5.3666(9) Å
7.8306(13) Å
8.5240(14) Å
115.552(2) °
106.336(3) °
93.256(3) °
303.49(9) Å3
1
References and notes
102.710(3)°
90°
1. Solomon, E. I.; Szilagyi, R. K.; George, S. D.; Basumallick, L. Chem. Rev. 2004, 104,
419.
Volume
Z
1557.2(2) Å3
4
2. (a) Krylova, K.; Kulatilleke, C. P.; Heeg, M. J.; Salhi, C. A.; Ochrymowycz, L. A.;
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2003, 8, 1577.
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Trans. 1976, 11, 939; (d) White, V. A.; Long, N. J.; Robertson, N. Org. Biomol.
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A.; Rorabacher, D. B. J. Chem. Soc., Dalton Trans. 2002, 792; (c) McAuley, A.;
Subramanian, S. Inorg. Chem. 1990, 29, 2830; (d) Blake, A. J.; Danks, J. P.; Fallis, I.
A.; Harrison, A.; Li, W.; Parsons, S.; Ross, S. A.; Whittaker, G.; Schröder, M. J.
Chem. Soc., Dalton Trans. 1998, 3969.
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Index ranges
1.283 Mg mÀ3
0.406 mmÀ1
128
1.388 Mg mÀ3
0.674 mmÀ1
696
0.34 Â 0.18 Â 0.09 mm3 0.47 Â 0.15 Â 0.14 mm3
À7 6 h 6 7
À10 6 k 6 10
À11 6 l 6 11
2721
À9 6 h 6 7
À15 6 k 6 11
À18 6 l618
10183
2756
[R(int) = 0.0352]
2756/0/162
Reflections collected
1412
[R(int) = 0.0270]
1412/0/68
Independent reflections
Data/restraints/
parameters
Goodness-of-fit on F2
1.064
R1 = 0.0381
wR2 = 0.0943
0.705
Final R indices [I >
r
(I)]
R1 = 0.0311
wR2 = 0.0765
R1 = 0.0498
wR2 = 0.0921
R indices (all data)
R
1 = 0.0401
wR2 = 0.0964
Largest diff. peak and
hole
0.412 and À0.347 e ÅÀ3 0.284 and À0.232 e ÅÀ3
7. (a) Lovecchio, F. V.; Gore, E. S.; Busch, D. H. J. Am. Chem. Soc. 1974, 96, 3109; (b)
Thompson, J. S.; Marks, T. J.; Ibers, J. A. J. Am. Chem. Soc. 1979, 101, 4180; (c)
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John Wiley & Sons, Ltd, 2006; (b) Westerby, B. C.; Juntunen, K. L.; Leggett, G. H.;
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A.; Rorabacher, D. B. Inorg. Chem. 1991, 30, 2109.
Table 2
Key bond distances and angles for L3 and L3.2HCl
Bond
lengths, Å
L3
L3Á2HCl
S–C
1.8117(16),
1.807(2), 1.820(3),
1.8154(16)
1.807(2), 1.817(2)
N–C
C–C
1.459(2), 1.461(2)
1.522(2), 1.528(2),
1.523(2)
1.501(3), 1.497(3), 1.491(3), 1.501(3)
1.521(3), 1.519(3), 1.524(3),
1.520(3)1.512(3), 1.524(3),
10. Micheloni, M.; Paoletti, P.; SiegfriedHertli, L.; Kaden, T. A. J. Chem. Soc., Dalton
Trans. 1985, 6, 1169.
Bond
angles°
C–S–C
C–N–C
C–C–S
11. (a) Abbas, A. A. J. Heterocyclic Chem. 2007, 44, 651; (b) Wilson, J. M.; Giordani,
F.; Farrugia, L. J.; Barrett, M. P.; Robins, D. J.; Sutherland, A. Org. Biomol. Chem.
2007, 5, 3651; (c) Quevedo, R.; González, M.; Díaz-Oviedo, C. Tetrahedron Lett.
2012, 53, 1595; (d) Caravan, P.; Ellison, J. J.; McMurray, T. J.; Lauffer, R. B. Chem.
Rev. 1999, 99, 2293; (e) Busch, D. H. Acc. Chem. Res. 1978, 1, 392; (f) Alexander,
V. Chem. Rev. 1995, 95, 273; (g) Glenny, M.; Lacombe, M.; Love, J. B.; Blake, A. J.;
Lindoy, L. F.; Luckay, R. C.; Gloe, K.; Antonioli, B.; Wilson, C.; Schröder, M. New.
J. Chem. 2006, 30, 1755; (h) Alcaro, M. C.; Orfei, M.; Chelli, M.; Ginanneschi, M.;
Papini, A. M. Tetrahedron Lett. 2003, 44, 5217; (i) Gu, S.; Kim, H.; Lee, G.; Kang,
B.; Chang, Y.; Kim, T. J. Med. Chem. 2011, 54, 143; (j) Truffer, S.; Ianoz, E.; Lerch,
P. Anal. Chim. Acta. 1988, 149, 217; (k) Bridger, G. J.; Skerlj, R. T.; Padmanabhan,
S.; Martelluci, S. A.; Henson, G. W.; Struyf, S.; Witvrouw, M.; Schols, D.; De
Clercq, E. J. Med. Chem. 1992, 42, 3971.
100.71(7)
102.47(12), 102.09(12)
117.23(19), 116.30(19)
113.32(17), 114.43(17),
112.27(16), 114.91(17)
110.0(2), 109.4(2)
112.48(12)
114.74(11),
110.37(11)
114.68(13)
111.76(13),
110.94(13)
C–C–C
N–C–C
111.28(19), 112.8(2), 110.94(19),
112.23(19),
corners. Similar crystallographic data of the tetra-protonated form
[H4(cyclam)]4+ were also reported by Raston.24 A comparison of L3
and L3Á2HCl crystal data and structure refinement parameters are
given in Table 1 and key bond distances and angles are reported
in Table 2.
In conclusion we have successfully synthesized ligand L3 in
good overall yield. Ligand L3 is currently undergoing copper and
chelation studies, and is also being employed as the framework
for the syntheses of several cryptands. These studies will be re-
ported in due time.
12. Siegfried, L.; Kaden, T. A. Helv. Chim. Acta 1984, 67, 29.
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Wild, S. B. Inorg. Chem. 1987, 26, 2963.
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Parker, David Macrocycle Synthesis: A Practical Approach; Oxford University
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M. Z. J. Chem. Soc. 1949, 892.
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Acknowledgments
We wish to thank The Goodyear Corporation for donation of the
NMR instrument, National Science Foundation (CHE-0116041) and
the Ohio Board of Regents for funds used to purchase the Bruker-
Nonius Apex CCD X-ray diffractometer. We also wish to thank
19. Oi, R.; Sharpless, K. B. Tetrahedron Lett. 1991, 32, 4853.
20. (a) Black, D.; McLean, I. A. Aust. J. Chem. 1971, 24, 1401; (b) Butler, J.; Kellogg, R.
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Bolhuis, F. J. Chem. Soc., Chem. Commun. 1990, 3, 282; (d) Kruizinga, W. H.;

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Kellogg, R. M. J. Am. Chem. Soc. 1981, 103, 5183; (e) Buter, J.; Kellogg, R. M. J.
Org. Chem. 1981, 46, 4481.
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Narasimhan, S. J. Org. Chem. 1982, 47, 3153.
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Bailey, N.; Schneider, H. J. Chem. Soc. Perkin Trans. 2 1990, 9, 1523.
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