Synthesis, characterization, and copper(II) chelates of 1,11-dithia-4,8-diazacyclotetradecane

Article abstract of DOI:10.1021/acs.joc.9b01682

Synthesis of 1,11-dithia-4,8-diazacyclotetradecane (L1), a constitutional isomer of the macrocyclic [14]aneN₂S₂ series, is accompanied with reaction and method optimization. Chelation of L1 with copper(II) provided assessment of latt

Full text of DOI:10.1021/acs.joc.9b01682

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Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Synthesis, Characterization, and Copper(II) Chelates of 1,11-Dithia-
4,8-diazacyclotetradecane
Ian S. Taschner,*,† Tia L. Walker,† Hunter S. DeHaan,† Briana R. Schrage,‡ Christopher J. Ziegler,‡
and Michael J. Taschner‡
†Department of Chemistry, Indiana University Northwest, Gary, Indiana 46408, United States
‡Department of Chemistry, The University of Akron, Akron, Ohio 44325, United States
S
* Supporting Information
ABSTRACT: Synthesis of 1,11-dithia-4,8-diazacyclotetrade-
cane (L1), a constitutional isomer of the macrocyclic
[14]aneN2S2 series, is accompanied with reaction and method
optimization. Chelation of L1 with copper(II) provided
assessment of lattice packing, ring contortion, and evidence
of conformational fluxionality in solution through two unique
crystal structures: L1Cu(ClO4)2 and [(L1Cu)2μ-Cl](ClO4)3.
Multiple synthetic approaches are presented, supplemented
with reaction methodology and reagent screening to access [14]aneN2S2 L1. Reductive alkylation of bis-tosyl-cystamine was
integrated into the synthetic route, eliminating the use and isolation of volatile thiols and streamlining the synthetic scale-up.
Late-stage cleavage of protecting sulfonamides was addressed using reductive N−S cleavage to furnish macrocyclic freebase L1.
prompted the design of a direct synthetic pathway to target
macrocycle L1. Chelation of copper(II) in the presence of L1
provided crystallographic information to compare against L3.
The copper(I/II) chelates of macrocycle L3 have been
analyzed by Walker et al. providing binding constants with
corresponding crystallographic structures assessing metal
geometry and bond distances.13
The simple structural motifs of the macrocyclic isomers,
L1−L3, can be synthetically deceptive due to the high variance
of possible chemical manipulations. The tendency for macro-
cyclizations to produce complex reaction mixtures through
kinetic oligomerization and polymerization provides an
additional challenge for the synthetic optimization of these
systems. Structural topology with respect to heteroatom
placement was determined to dramatically influence a late-
stage reductive N−S cleavage reaction and purification. Three
synthetic strategies were implemented to afford [14]aneN2S2
L1, accompanied by reaction optimization and topological
contrasts between constitutional macrocyclic isomer L3.
INTRODUCTION
■
Mixed N, S-containing macrocyclic ligands continue to be of
significant interest due to their metal chelate coordination and
redox properties with d-block elements.1 The property of the
[14]aneN2X2 series (X = S or O) to chelate both hard and soft
metals has been reported throughout the literature2 with
recently reporting as biological CO2- and proton-reducing
agents,3 MRI contrast agents,4 positron emission tomography
imaging,5 anticancer agents,6 nitric oxide sensors,7 and as a
scaffold for cryptand formation.8 Many copper(II) chelates
within the [14]aneN2S2 series have been previously inves-
tigated by both Rorabacher and Siegfried with binding
constants and comparisons to other mixed [14]ane systems
including S4 and N4.9 Practical pathways leading to the
synthesis of [14]aneN2S2 L210 and L311 heteroconstitutional
isomers (Figure 1) have been previously reported in moderate
and reproducible yields.
Although the use and application of heteromacrocycle L1
have been mentioned in the literature,3,12 a descriptive
synthetic strategy and characterization have been omitted
including X-ray diffraction data for copper chelation. This
DISCUSSION
■
The strategic pathway toward L1 was initially assumed to be a
simple four-step linear sequence, in which the macrocyclization
of bis-acid chloride derived from bis-COOH 2 to the
corresponding bis-lactam 1 would be the bottleneck reaction
(Scheme 1). Reduction with borane followed by hydrolysis of
the N−B bond would provide macrocycle L1 efficiently with
minimal chemical manipulations (Method 1). A second
method was designed around macrocyclic sulfonamide 3,
Received: June 23, 2019
Figure 1. [14]aneN2S2 heteroconstitutional isomers.
© XXXX American Chemical Society
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Scheme 1. Retrosynthetic Proposals toward the Synthesis of
L1
Table 1. Reaction Optimization of Bis-lactam 1
molarity
%
yield
(1,3-diaminopropane)
molarity 6 solvent
base
0.05
0.05
0.01
0.05
0.05
0.01
0.01
0.01
0.05
0.01
0.05
0.05
0.01
0.05
0.05
0.01
0.01
0.01
0.05
0.01
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Et2O
Et2O
Cs2CO3
K2CO3
NEt3
K2CO3
Cs2CO3
K2CO3
Cs2CO3
K2CO3
NEt3
10
18
22
12
7
15
12
17
20
37
Et2O
PhMe
PhMe
PhMe
NEt3
quantities. Modulating the temperature during the course of
the reaction provided no appreciable yield of lactam 1; higher
temperatures (>35 °C) provided oligomers, and at lower
temperatures (<5 °C), bis-acid 2 was the major component,
even after 72 h.
Reduction of amides to their corresponding amines with
borane dimethyl sulfide (BDS) has been previously performed
with high yields during the preparation of macrocycle L3.11
When lactam 1 was subjected to a BDS reduction, the majority
of the mass was composed of byproducts following a difficult
purification of macrocycle L1. Additionally, the cleavage of the
nitrogen−boron adducts with methanol/triethanolamine con-
tributed to low yields and long reaction times invoking a
change in reaction conditions. Switching to LAH provided no
further increase in the yield or purity of L1. With the last two
synthetic steps being tedious and low yielding (see Scheme 2),
an alternative route was established.
The second method was performed in four sequential steps
starting from bis-sulfonamide 7, providing a 48% overall yield
of heteromacrocycle L1. Sulfonamide 7 was subjected to bis-
hydroxyethylation through a KOH (20%)/ethylene carbonate
melt affording the desired bis-hydroxyethyl sulfonamide 8a
along with monoalkylated sulfonamide 8b and overalkylated
ether 8c (Scheme 3). This method was optimized (Table 2)
through stoichiometric and temperature screening to obtain
bis-hydroxyethyl sulfonamide 8a in 89%. Crystal and structure
refinement data are located in the Supporting Information for
this manuscript.
which allowed two different modes for macrocyclization. The
first mode (Method 2a) was envisioned to take advantage of
sulfur’s nucleophilicity for governing the macrocyclization of
bis-chloride 4. The second mode (Method 2b) of macro-
cyclization incorporating bis-sulfonamide 5 proved to be
comparable in yield and was much more applicable to scale-
up. Removal of sulfonamides (N−S cleavage) through known
N−S cleavage reactions would provide pure L1. The use of
different pathways to obtain heteromacrocycle L1 provides
multiple ways to construct analogs and design larger
macrocycles. Overall yields of [14]aneN2S2 L1 using methods
1, 2a, and 2b were 7, 48, and 52%, respectively.
The initial approach (Method 1) proceeded through a four-
step sequence, in which the final borane reduction of bis-
lactam 1 afforded macrocycle L1. Synthesis of bis-lactam 1 was
synthesized through a tandem N-acylation−macrocyclization
from a bis-acid chloride derived from carboxylic acid 2
(Scheme 2). Lactam 1 has been prepared previously by
Bradshaw et al. through a tandem bis-alkylation of 1,3-
propanedithiol and a symmetric α-chloroacetamide in a 31%
yield; however, reduction to L1 was not reported.14
Reaction optimization for the synthesis of bis-lactam 1 from
bis-acid chloride 6 was implemented using high dilution, as
well as the slow simultaneous addition of the electrophile and
nucleophile from separate syringe pumps to provide a
maximum yield of 37% (average yield ∼ 26%) (Table 1).
This method of reactant addition during macrocyclizations has
been implemented to thwart oligomerization and provide
ample time for the intramolecular cyclization. The use of
nonpolar and nonprotic solvents provided 1 in isolable
Interestingly, the bis-hydroxyethylation resulted in a
dramatic increase in the yield of hydroxyethyl sulfonamide
8a between temperatures 100 and 115 °C (Table 2).
Scheme 2. Initial Synthetic Approach to the Synthesis of L1
B
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Scheme 3. Method 2a Synthetic Approach to L1. To Enhance Clarity of Thermal Ellipsoids, H Atoms on Carbon Have Been
Omitted
separation of 8a−8c. The addition of potassium hydroxide
above the catalytic 10% did not increase reaction rate or yield.
The use of thionyl chloride provided bis-chloroethyl
sulfonamide 4 in high yield (Scheme 3). This compound
was crystallographically characterized, and the solution is
available in the Supporting Information section.
Table 2. Hydroxyethylation Reaction Optimization (4 h, 10
wt % KOH) Performed with 1 mmol of Bis-sulfonamide 7
ethylene carbonate
(Eq)
temperature
% yield
% yield
% yield
a
a
a
(°C)
8a
8b
8c
2
3
4
5
5
5
5
190
170
150
130
125
115
110
19
20
29
47
47
89
52
0
5
5
5
12
5
30
31
20
12
12
1
The formation of macrocyclic sulfonamide 3 proceeded
through nucleophilic addition followed by intramolecular
macrocyclization. This was carried out using the modified
dilution/addition conditions outlined by Dietrich and Lehn.15
To increase reaction precision, reduce byproducts, and
increase yields, dichloride 4 and propanedithiol were combined
and added simultaneously to cesium carbonate in DMF at ∼95
°C to provide macrocycle 3 in a 68% yield. The use of cesium
carbonate during macrocyclizations has shown to increase
yields through a template effect,16 serendipitously switching to
potassium carbonate furnished macrocycle 3 in similar yields
20
0
a
Isolated yields.
Chromatographic separation of sulfonamides 8a−8c was
relatively tedious, used large amounts of the mobile phase,
and appeared to have high retention to the stationary silica
when using traditional ethyl acetate:hexane solutions.
Purification using smaller quantities of mobile phase was
remedied through the use of toluene:acetone, providing
1
with a clean reaction profile observed in the crude H NMR.
The use of cesium as a counter cation for template-driven
macrocyclizations has been reported in the literature and is
Scheme 4. Cystamine-Based Synthesis of Macrocycle L1
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observed with oxygen-based heterocycles. When replacing the
heteroatom to sulfur, this metal-template effect is diminished,
presumably by the tendency for sulfide linkages to orient
themselves in an exodentate fashion, directing lone pairs away
from the center as shown with other metals.17 The entropic
reordering of sulfides is not energetically favorable and can
cause metal ions to bridge the macrocycle instead of chelation
within the cavity. Buter and Kellogg demonstrated that a high-
yield cyclization of 1, ω-dithiols with 1, and ω-dihalides ruled
out any template effect.18 However, cesium carbonate did not
surpass potassium carbonate in cyclization yields in DMF,
suggesting that cesium is not critical in this case.
To eliminate the use of volatile thiols as reagents and
provide a practical scale-up, Method 2b was pursued (Scheme
4). Starting from tosyl-cystamine (9), a triphenyl phosphine
(TPP)-mediated reductive alkylation afforded acyclic bis-
sulfide 5 in moderate yields. Separation of bis-sulfide 5 from
triphenyl phosphine oxide (TPPO) byproduct proved difficult
and often required two silica-based chromatographic separa-
tions. The use of ethanol and zinc chloride precipitated out
∼90% of TPPO as Zn(TPPO)2Cl2 complex, allowing for
effective purification and isolation (Table 3).19
Figure 2. Proposed thiol−disulfide exchange modeled after
posttranslational modification of cysteine by Gilbert.20
phosphine (TCEP) for reductive alkylation allowed for scale-
up, simple aqueous workup, and elimination of column
chromatography before macrocyclization. Acyclic, bis-sulfide
5 was subjected to macrocyclization conditions through
substitution with the sulfonamide nitrogen atoms. Macrocycle
3 was obtained in a 51% yield through sulfonamide ring
closure and then subjected to N−S cleavage conditions to
obtain heteromacrocycle L1.
Reductive desulfonylation of sulfonamides to their corre-
sponding free amines is reported throughout the literature,
using a multitude of conditions ranging from sonication in
methanol/magnesium to HBr/acetic acid.21 Many conditions
are either too harsh resulting in decomposition/low yields or
no reaction with the starting material remaining intact (Table
4). Interestingly, heteromacrocycles L1, L2, and L3 were
Table 3. Reaction Conditions for the Formation of 5
yield of 5
(%)
conditions
(a) TPP, reflux (b) NaOH, 1,3-dibromopropane (c) ZnCl2,
EtOH
(a) TPP, reflux (b) K2CO3, 1,3-dibromopropane (c) ZnCl2,
EtOH
(a) DTT, K2CO3, reflux (b) K2CO3, 1,3-dibromopropane
(a) DTT, NaOH, reflux (b) NaOH, 1,3-dibromopropane
(a) PBu3, reflux (b) NaOH, 1,3-dibromopropane
(a) PBu3, reflux (b) K2CO3, 1,3-dibromopropane
(a) TCEP, NaOH, reflux (b) NaOH, 1,3-dibromopropane
(a) TCEP, NaOH, reflux (b) NaOH, 1,3-ditosylpropane
82
80
81
72
88
79
91
68
The major drawback was determined during scale-up using
TPP, where ∼10% of the TPPO is still present in solution
causing contamination during chromatographic separation.
Attempts to subject the solution with ∼10% TPPO to more
zinc chloride did not initially show any precipitation; however,
after 72 h at 0 °C, small amounts of zinc−TPPO complex
precipitated out allowing for acyclic bis-sulfide 5 purification.
In an attempt to eliminate TPPO contamination and use an
aqueous workup for purification, tosyl-cystamine (9) was
subjected to dithiothreitol (DTT) as the reductant.
Table 4. Desulfonylation Conditions and Isolated Yields
yield of L1
(%)
yield of 10
recovery of 3
(%)
a
conditions
(%)
Mg/methanol/
sonication
Na2K/THF/23 °C
K2Na/THF/23 °C
NaK2 stage I/THF/
23 °C
2b
0
93
2b
0
0
0
0
90
89
91
0
Issues regarding the use of DTT were observed during the
alkylation with 1,3-dibromopropane. Both sodium thiolate
molecules derived from DTT and tosyl-cystamine 9 have the
potential to perform substitution, lowering the yield of 5.
Reducing the equivalents of DTT (1.3 equiv with respect to
9), disulfide cleavage provided an increase in the yield of bis-
sulfide 5 but was difficult to chromatographically separate from
byproducts. Mixed S-alkylations were attributed to thiol−
disulfide exchange between thiolate derived from tosyl-
cystamine and the oxidized cyclic disulfide originated from
DTT (Figure 2).20
Switching to tributyl phosphine (PBu3) as the reductant
provided 5 in an 88% yield with simple chromatographic
separation (Table 3). Additionally, the disulfide cleavage with
PBu3 was completed within 25 min with no observable
disulfide detected via TLC. The use of tris(carboxyethyl)-
HBr/HOAc/reflux
HBr/HOAc/23 °C
Na°/naphthalene/
−50 °C
Red-Al/xylenes/reflux
SmI2/THF
5−10
0
89
5−10
10
0
0
41
0
38b
0
30
0
0
95
a
1
Yield determined through H NMR.
isolated in optimal yields through differing detosylation
conditions establishing a reagent bias with respect to
heteroatom placement along the [14]aneN2S2 backbone.
Most cleavage conditions attempted on macrocycle 3 failed
to produce macrocycle L1. Red-Al (vitride) was the first
reagent that provided L1 in ∼30% yield. A major limitation of
this reduction was the presence of the mono-tosyl 10 (isolated
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Figure 3. Detosylation reaction conditions of three heteroconstitutional isomers 3, 11, and 12.
as the HCl salt) that was difficult to remove through
chromatographic separation. The use of sodium naphthalenide
to perform the N−S bond cleavage afforded [14]aneN2S2 L1
cleanly over a 15 min period at −35 °C. Due to the freebase
instability in the presence of oxygen and carbon dioxide,
macrocyclic salt L1-HCl was initially made for storage
purposes and maintained at −20 °C. The analysis of L1-HCl
through 1H and 13C NMR provided frequency-resolved
spectra, unlike the macrocyclic L1 freebase that is composed
of overlapping resonances.
For comparative desulfonylation conditions within the
[14]aneN2S2 family, L2 and L3 were produced following the
procedures outlined by Ochrymowycz et al.,10 Bridger et al.,22
and Walker et al.11 (Figure 3). Two procedural modifications
were performed for the synthesis of macrocycle L2 following
Bridger’s method and are reported in the Experimental
Section. This included a bis-Michael addition mediated
through sonication affording bis-nitrile 13 (Supporting
Information) along with a Red-Al detosylation on substrate 12.
Switching desulfonylation conditions to refluxing Red-Al in
xylenes afforded L2 in near-quantitative yields and required no
extensive purification, with the exception of acid/base workup.
The analysis of [14]aneN2S2 L2 through NMR spectroscopy
proved troublesome as the resonances were overlapping, as
seen with [14]aneN2S2 L1. The hydrogen chloride salt L2-HCl
was used to provide frequency-resolved NMR spectra in
deuterium oxide.
Heteroatom placement in the backbone of [14]aneN2S2
macrocycle systems imparts a significant role for the preference
of reagents on the cleavage of the N−S system. Although many
desulfonation conditions provided the freebase ligands (L1,
L2, and L3), the isolated yields were negligible unless the
appropriate conditions were applied. Topologic and heter-
oatom placements intrinsic to each sulfonamide with respect to
the adjacent nitrogen and sulfur atoms could explain the
variance in reagents with respect to isolated yield.
Due to the instability of L1 freebase, the diprotonated
species of L1-HCl was immediately formed and stored at ∼0
°C. Crystal structures of L1-HCl were obtained through the
slow evaporation of methanol (Figure 4) with significant bond
Figure 4. Thermal ellipsoid diagram of L1-HCl salt with 35%
probability displacement ellipsoids. C−H hydrogen atoms are omitted
for clarity. The trans-L3-HCl, previously reported, was used for
comparison (CCDC 888496).11
lengths and bond angles shown in Table 5. Crystal and
structure refinement data for L1-HCl are located in the
Supporting Information. Compound L2-HCl failed to produce
crystals, and the previously elucidated L3-HCl is shown for
comparison. L3-HCl was reported to adopt a rectangular
endodentate conformation with heteroatom placement at the
four corners of the ring, resulting in the asymmetrical crown.11
The bond length and bond angles of L1-HCl compared to
those of L3-HCl are not statistically different; therefore, the
structural conformations may be explained by the packing
forces and crystal symmetry (see Supporting Information).
Ligand L1-HCl was expected to adopt a preferred [3434]
conformer (Dale notation)23 similar to L3-HCl; however, the
conformational assessment indicated a [3335] arrangement.
Crystallographic Data and Copper(II) Chelation.
Crystallographic elucidation of L1 with copper(II) is lacking.
With access to the freebase, reaction with Cu(ClO4)2·6H2O in
CH3CN at ambient conditions with L1 resulted in a deep
purple color, which unlike the reported L3 did not precipitate
out. Slow evaporation at 4 °C produced two distinct unit cell
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Table 5. Selected Bond Angles and Bond Lengths for Ligands L1-HCl and L3-HCl
bond
angles, deg
bond lengths, Å
L1-HCl
L3-HCl
L1-HCl
L3-HCl
S−C
1.8106(17), 1.8152(17),
1.8194(19), 1.8174(17)
1.807(2), 1.820(3),
1.807(2), 1.817(2)
C−S−C
101.87(8), 101.79(8)
102.5(12), 102.1(12)
N−C
1.4973(19), 1.5024(18),
1.5077(19), 1.4988(19)
1.501(3), 1.497(3),
1.491(3), 1.501(3)
C−N−C
C−C−S
115.09(12), 116.26(11)
117.2(19), 116.3(19)
111.18(11), 112.04(11),
116.92(12), 114.29(12)
113.3(17), 114.4(17),
112.3(16), 114.9(17)
C−C−C
N−C−C
112.80(12), 113.30(15)
112.21(13), 111.25(12),
114.73(12), 109.78(12)
110.0(2), 109.4(2)
111.3(19), 112.8(2),
110.9(19), 112.2(19)
Figure 5. Thermal ellipsoid diagrams of two separate conformations of L1 copper complexes, [(L1Cu)2μ-Cl](ClO4)3, L1Cu(ClO4)2, and
previously reported L3Cu(ClO4)2, (CCDC 905763)11 at 35% probability displacement ellipsoids. All C−H hydrogen atoms are omitted for clarity,
and [(L1Cu)2μ-Cl](ClO4)3 is shaded for comparison in the conformational structure to L1Cu(ClO4)2.
Table 6. Selected Bond Angles and Bond Lengths for Copper Complexes
[(L1Cu)2μ-Cl](ClO4)3
Bond Lengths, Å
L1Cu(ClO4)2
L3Cu(ClO4)2
S−C
1.822(3), 1.814(3), 1.824(3), 1.822(4), 1.822(3), 1.811(3), 1.818(3), 1.807(4)
1.468(4), 1.490(4), 1.488(4), 1.482(4), 1.486(4), 1.480(4), 1.486(4), 1.473(4)
2.025(3), 2.027(3), 2.028(3), 2.027(3)
1.816(17), 1.806(15)
1.44(2), 1.48(2)
2.008(15)
1.816(2), 1.816(2)
1.492(2), 1.500(2)
2.014(17)
N−C
N−Cu
S−Cu
2.3332(9), 2.3407(9), 2.3324(9), 2.3374(10)
2.315(4)
2.295(8)
Bond Angles, deg
C−S−C
C−N−C
C−C−S
C−C−C
N−C−C
N−Cu−N
S−Cu−S
S−Cu−N
102.94(16), 103.21(16), 102.22(16), 102.74(15)
110.5(3), 111.2(3), 111.3(3), 110.9(3)
112.4(2), 111.5(2), 106.1(2), 107.7(2), 112.4(2), 110.1(2), 106.4(2), 106.7(2)
116.0(3), 115.1(3), 115.3(3), 115.7(3)
109.8(3), 111.4(3), 111.6(3), 109.3(3), 109.6(3), 112.6(3), 111.2(3), 109.9(3)
92.54(11), 91.77(11)
89.93(3), 90.71(3)
102.6(8)
112.6(15)
109.1(12), 111.6(13)
116(2), 117.0(18)
111.4(18), 112.2(15)
101.0(9)
105.6(9)
108.0(14)
105.6(13), 108.3(13)
115.1(16)
110.9(15), 114.9(16)
180.0(22)
85.8(2)
86.5(5), 171.6(5)
179.9(11)
87.9(5), 92.0(5)
87.77(8), 168.85(8), 167.66(8), 87.40(8), 87.43(8), 168.35(8), 167.57(8), 87.58(8)
crystals suitable for X-ray diffraction (Figure 5) with crystal
and refinement data, reported in the Supporting Information.
All three systems exhibit planar coordination environments
with respect to the metal center including comparable bond
lengths and angles (Table 6).
Chelate [(L1Cu)2μ-Cl](ClO4)3 has S−Cu−N bond angles
averaging 168° due to the bridging three-center, four-electron
chloride atom compared to those of 172 and 180° for
L1Cu(ClO4)2 and L3Cu(ClO4)2, respectively. More notably,
L1Cu(ClO4)2 differs from [(L1Cu)2μ-Cl](ClO4)3, in that the
N−H bonds orientate opposite the sulfur lone-pair electrons.
Both crystal packing and a bridging chloride atom induce
changes in the ligand coordination, indicating that the binding
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nitrogen. Dimethylformamide was distilled from calcium hydride
under vacuum and stored over 3 Å molecular sieves and degassed with
argon using a gas dispersion frit. Reactions run at room temperature
conformation of L1 is perhaps quite flexible and fluxional in
solution.
Coordination of ligands L1 and L3 to copper(II) does,
however, produce noteworthy structural changes. In both
[(L1Cu)2μ-Cl](ClO4)3 and L1Cu(ClO4)2, the coordination
of copper to both sulfur atoms exhibits a low strain chair
conformation as compared to the torsion angles of cyclo-
hexane24 with the connecting five-membered chelate in a
favorable equatorial position. However, in the case of
L1Cu(ClO4)2, the coordination of copper to nitrogen induces
a conformation similar to a distorted envelope.24
The copper(II)−thioether bonds are quite short (∼2.3 Å) in
both [(L1Cu)2μ-Cl](ClO4)3 and L1Cu(ClO4)2, suggesting
that the bond orientation is overlapping with the magnetic
orbital of copper(II).25 Qualitative analysis depicted an
observable difference with respect to the lone pairs on sulfur
and the protons attached to the nitrogen atoms. As the lone
pairs on sulfur are diffuse and flexible, L1Cu(ClO4)2 seemed
to perform a pseudo-chair flip with respect to ligand−metal
chelate [(L1Cu)2μ-Cl](ClO4)3, which will be further inves-
tigated.26
Ultraviolet−visible spectroscopy of L1Cu(ClO4)2 provided
λmax of 275, 335, and 535 nm in aqueous solution, comparable
to the previously reported data.12d A slight blue shift was
observed with L1Cu(ClO4)2 compared to that of L3Cu-
(ClO4)2 (295, 354, and 545 nm) due to heteroatom
positioning (Supporting Information). The band at 535 nm
corresponds to the (N) → Cu(II) ligand-to-metal charge
transfer (LMCT), and the most intense absorption at 335 nm
results from the (S) → Cu(II) LMCT.9 Spectrochemical
comparison with copper(II) chelates of [14]aneN4 (cyclam),
[14]aneS4, and [14]aneN2S2 isomers (L1 and L3) provided
weaker ligand field bands associated with the sulfur-based
systems, which corroborates the Kauffman et al. analysis of
sulfide donation and configuration.12d,27
1
are in the range of 22−24 °C. H and 13C NMR were obtained on a
Varian 400 spectrometer as solutions in CDCl3 with and without
TMS and referenced to the CHCl3 residual protioisomer. For spectra
1
taken in other NMR solvents, D2O, and DMSO-d6, the H spectra
were referenced to the solvent residual protioisomers, and 13C spectra
were referenced to the NMR solvent. Chemical shifts are expressed in
parts per million values, and coupling constants (J) are reported in
Hertz (Hz) and rounded to the nearest 0.5 Hz. The following
abbreviations are used to indicate apparent multiplicities: s, singlet; d,
doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets;
t, triplets; q, quartets; m, multiplet. Flash column chromatography on
silica gel (60 Å, 230−400 mesh, low acidity, obtained from EMD
Millipore Corporation) was performed using reagent-grade solvents.
Analytical thin-layer chromatography (TLC) was performed on
precoated aluminum-backed silica gel plates (EMD Millipore
Corporation) and visualized with a UV lamp (254 nm) or an
iodine/silica or potassium molybdic acid solution in ethanol or
KMnO4(aq) or p-anisaldehyde(EtOH) or vanillin(EtOH)
.
PHYSICAL METHODS
■
For temperature control in tandem with the reaction, mixing an Ika
RCT digital stir plate with a PT 10000.60 temperature probe was
used. FTIR spectra were collected on a Jasco 4600 spectrophotometer
running the Spectra Manager CFR, where samples were prepared as a
neat oil or solid on a ZnSe window using attenuated total reflectance
(ATR). Melting points were obtained on a MeltTemp melting point
apparatus and are uncorrected.
High-resolution mass spectra (HRMS) were recorded on a time-of-
flight JMS-T1000LC spectrometer with a DART ion source. ESI-MS
spectra were acquired with a Bruker micrOTOF II, in the positive
mode (parent ion plus H+). ESI samples were prepared for analysis by
dissolving samples to 10−4 M in acetonitrile and were directly infused
into the mass spectrometer at a flow rate of 4 μL/min. The ESI was
operated with a capillary offset of 4500 V and a skimmer potential of
48 V. The samples were calibrated using an internal standard.
X-ray intensity data were measured on a Bruker CCD-based
diffractometer with a dual Cu/Mo ImuS microfocus optics (Cu Kα
radiation, λ = 1.54178 Å, Mo Kα radiation, λ = 0.71073 Å). Crystals
were mounted on a cryoloop using Paratone oil and placed under a
steam of nitrogen at 100 K (Oxford Cryosystems). The detector was
placed at a distance of 5.00 cm from the crystal. The data were
corrected for absorption with the SADABS program. The structures
were refined using the Bruker SHELXTL software package (version
6.1) and were solved using direct methods until the final anisotropic
full-matrix, least-squares refinement of F2 converged.
UV and visible spectra in solution were run in 1 cm cells using a
Perkin Elmer Lambda 365 UV−vis spectrometer at concentrations
appropriate for measurements of absorption bands, and the data
collection was obtained at ambient temperatures.
The Supporting Information (CCDC 1912553-1912560) contains
the supplementary crystallographic data for this article. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1,11-Dithia-4,8-diazacyclotetradecane-3,9-dione (1). A 250
mL flame-dried three-neck round-bottom flask equipped with a
magnetic stir bar, a nitrogen inlet, and three septa was charged with
dry toluene (100 mL). A syringe was charged with 1,3-
diaminopropane (0.14 mL, 1.60 mmol) and triethylamine (0.47
mL, 3.36 mmol) in toluene (40 mL), and a second syringe was
charged with 2,2′-(propane-1,3-diylbis(sulfanediyl))diacetyl chloride
(6) (0.428 g, 1.60 mmol) in toluene (40 mL); these two solutions
were attached to individual syringe pumps and added to the
vigorously stirring toluene at a rate of ∼1 drop per 10 s
simultaneously. After the addition of the reagents, the solution was
allowed to stir for a 12 h period. This solution was then concentrated
in vacuo and immediately subjected to column chromatography
CONCLUSIONS
■
In summary, the synthetic methodology implemented for the
synthesis of 1,11-dithia-4,8-diazacyclotetradecane (L1) has
been completed and optimized. This is the first detailed
synthesis of L1 reported to date, which allows for a multitude
of analogs to be tailored for select applications. This study
provides a practical approach to macrocycles containing aza/
thia heteroatoms and showcases the difference in reactivity
associated with the [14]aneN2S2 heteroconstitutional isomers.
A unique, efficient disulfide cleavage−alkylation mediated
through TCEP was explored and optimized to attain disulfide
5. This study expands upon the pioneering work performed by
Lehn and Cram for inter/intratandem macrocyclizations,
which implements high-dilution conditions and slow addition
of reagents. For detosylation of the resulting sulfonamides, it
was determined that some reagents were more amenable to
individual constitutional isomers. Currently, computational
assessments are underway to assess the fluxionality and
conformational bias between macrocyclic chelates L1Cu-
(ClO4)2 and [(L1Cu)2μ-Cl](ClO4)3. The ligands also have
the advantage of performing late-stage diversification, poten-
tially leading to biologically compatible motifs used in imaging.
EXPERIMENTAL SECTION
■
All commercial reagents, unless otherwise stated, were used as
received (Sigma-Aldrich, VWR, or Fischer Scientific Ltd.). Dichloro-
methane and acetonitrile were distilled from calcium hydride under
G
DOI: 10.1021/acs.joc.9b01682
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The Journal of Organic Chemistry
Article
1
(EtOAc) to provide bis-lactam 1 in a 37% yield (155 mg, 0.592
mmol) as an amorphous white residue. Rf = 0.3 (EtOAc); H NMR
145 °C. H NMR (400 MHz, chloroform-d) δ 7.67 (d, J = 8.5 Hz,
4H), 7.32 (d, J = 8.5 Hz, 4H), 3.22 (q, J = 6.9 Hz, 8H), 2.81 (t, J = 7.4
Hz, 4H), 2.63 (t, J = 6.7 Hz, 4H), 2.43 (s, 6H), 2.05 (p, J = 7.4 Hz,
2H), 1.91 (p, J = 6.6 Hz, 2H); 13C{1H} NMR (101 MHz, chloroform-
d) δ 143.6, 135.3, 129.9, 127.2, 49.8, 48.5, 31.9, 29.7, 29.7, 21.5. IR
νmax 2924, 2857, 1337, 1157, 1089, 815, 721, 653 cm−1. HRMS
(APCI) m/z [M + H]+ calcd for C24H35O4N2S4 543.1474, found
543.1477.
1
(400 MHz, chloroform-d) δ 7.07 (s, 1H), 3.48 (q, J = 5.8, 5.2 Hz,
2H), 3.25 (s, 2H), 2.71 (t, J = 7.0 Hz, 2H), 2.01−1.74 (m, 1H);
13C{1H} NMR (101 MHz, chloroform-d) δ 169.6, 39.7, 36.9, 32.3,
29.2, 28.9; IR νmax 3315, 3300, 2923, 2857, 1730, 1638, 1529, 1451,
1054 cm−1; HRMS (EI+) m/z [M + Na]+ calcd for C10H18O2N2NaS2
285.0702, found 285.0707.
N,N′-(Propane-1,3-diyl)bis(N-(2-chloroethyl)-4-methylben-
2,2′-(Propane-1,3-diylbis(sulfanediyl))diacetic acid (2). A 50
mL flame-dried round-bottom flask equipped with a magnetic stir bar
and a condenser was charged with 1,3-propanedithiol (1.00 mL, 9.96
mmol), ethanol (4.00 M, 2.49 mL), and sodium borohydride (0.0190
g, 0.498 mmol) in the indicated order. An aqueous potassium
hydroxide solution (2.50 mL, 16 M, 39.8 mmol) was added slowly to
the mixture (15 min). The addition of chloroacetic acid (1.88 g, 19.9
mmol) in ethanol (5.00 mL) was added dropwise over a period of 15
min, after which the solution was allowed to reflux for 12 h using a
heating mantle. The reaction mixture was then concentrated in vacuo
and dissolved in water (20 mL), and the impurities were washed out
with diethyl ether (2 × 3 mL). The aqueous layer was acidified to pH
∼1 with concentrated sulfuric acid. The product was extracted with
diethyl ether (3 × 20 mL). The combined ethereal layers were dried
with Na2SO4, filtered, and concentrated in vacuo. The residual oil was
taken up in toluene (30 mL) and allowed to crystallize over a 12 h
period at 0 °C. The bis-carboxylic acid was filtered off affording a
white solid (1.653 g, 7.37 mmol) in a 74% yield. Mp = 69−70 °C; 1H
NMR (300 MHz, deuterium oxide) δ 3.45 (s, 3H), 2.80 (t, J = 7.2 Hz,
4H), 1.98 (p, J = 7.2 Hz, 2H); 13C{1H} NMR (75 MHz, deuterium
oxide) δ 174.8, 33.3, 30.7, 27.6; IR νmax 2922, 2672, 1707, 1419, 1288,
1205, 1141 cm−1. HRMS (EI+) m/z [M + Na]+ calcd for
C7H12NaO4S2 247.0069, found 247.0062.
4,8-Ditosyl-1,11-dithia-4,8-diazacyclotetradecane (3). DMF
was degassed with nitrogen for ∼20 min via gas dispersion frit prior to
running the reaction, mitigating the possibility of disulfide formation.
Method A. A 100 mL three-neck round-bottom flask equipped with
a septum, a nitrogen inlet, a condenser, and a magnetic stir bar was
charged with anhydrous potassium carbonate (0.286 g, 2.07 mmol)
and DMF (20 mL). A separate 25 mL pear flask was charged with
DMF (10 mL), 1,3-propanedithiol (0.10 mL, 1.03 mmol), and bis-
chloroethyl sulfonamide 6 (0.50 g, 0.985 mmol). This flask was fitted
with an inlet line inserted through a septum from a fluid metering
pump, and the terminal line was fitted into a septum attached to the
three-neck round-bottom flask. The flask containing potassium
carbonate and DMF was heated to 90−95 °C via a heating mantle,
and the fluid metering pump was set to add the contents of the pear
flask into the three-neck round-bottom flask at a rate of 1 drop/8 s.
Once all of the contents from the pear flask were added, the reaction
was stirred at 90−95 °C for 12 h. After which the reaction was cooled
down to room temperature, the DMF was removed in vacuo, and the
residue was subjected to column chromatography (19:1; PhMe/
acetone) Rf = 0.4 (1:1 Hex/EtOAc) affording 3 (0.380 g, 0.670
mmol) in a 68% yield.
Method B. A 1 L two-neck round-bottom flask equipped with a
septum, a nitrogen inlet, a condenser, and a magnetic stir bar was
charged with anhydrous potassium carbonate (3.22 g, 23.31 mmol)
and DMF (155 mL). A separate 250 mL two-neck pear flask was
charged with DMF (78 mL), 1,3-dibromopropane (0.79 mL, 7.77
mmol), and N,N′-((propane-1,3-diylbis(sulfanediyl))bis(ethane-2,1-
diyl))bis(4-methylbenzenesulfonamide) (5) (3.91 g, 7.77 mmol).
This flask was fitted with an inlet line inserted through a septum from
a fluid metering pump, and the terminal line was fitted into a septum
attached to the 1 L two-neck round-bottom flask. The potassium
carbonate and DMF were heated via a heating mantle to 100 °C, and
the fluid metering pump was set to add the contents of the pear flask
into the two-neck round-bottom flask at a rate of 1 drop/8 s. Once all
of the contents from the pear flask were added, the reaction was
stirred at 100 °C for 24 h. After which the reaction was cooled down
to room temperature, the DMF was removed in vacuo, and the
residue was subjected to column chromatography (19:1; PhMe/
acetone) affording 3 (2.14 g, 3.96 mmol) in a 51% yield. Mp = 144−
a
zenesulfonamide) (4) . A flame-dried 25 mL round-bottom flask
equipped with a magnetic stir bar, a condenser, and a calcium sulfate
drying tube was charged with N,N′-(propane-1,3-diyl)bis(N-(2-
hydroxyethyl)-4-methylbenzenesulfonamide) (8) (1.49 g, 3.20
mmol) and thionyl chloride (5 mL). The reaction was refluxed on
a heating mantle for 12 h, at which time the reaction was cooled down
to room temperature and toluene (10 mL) was added and removed in
vacuo. The toluene (10 mL) washes were performed two additional
times to azeotropically remove the excess thionyl chloride. The yellow
oil was dissolved in minimal MTBE, and methanol or ethanol was
added until a thick white precipitate was observed. This was heated to
reflux and allowed to cool at −20 °C for 12 h to precipitate out the
final bis-alkyl chloride 4 (0.428 g, 2.94 mmol) in a 92% yield as a
1
white solid. Mp = 83−84 °C. Rf = 0.88 (EtOAc); H NMR (400
MHz, chloroform-d) δ 7.66 (d, J = 8.1 Hz, 4H), 7.31 (d, J = 8.4 Hz,
4H), 3.62 (t, J = 7.0 Hz, 4H), 3.35 (t, J = 7.0 Hz, 4H), 3.17 (t, J = 7.3
Hz, 4H), 2.41 (s, 6H), 1.88 (p, J = 7.3 Hz, 2H); 13C{1H} NMR (101
MHz, chloroform-d) δ 143.9, 135.6, 129.9, 127.2, 50.6, 47.7, 42.2,
28.7, 21.5. IR νmax 2975, 2933, 2877, 1732, 1597, 1455, 1402, 1337,
1249, 1208, 1154, 1117, 1089, 913, 727 cm−1; HRMS (ESI) m/z [M
+ Na]+ calcd for C21H28O4N2S2NaCl2 529.0760, found 529.0759.
N,N′-((Propane-1,3-diylbis(sulfanediyl))bis(ethane-2,1-
diyl))bis(4-methylbenzenesulfonamide) (5). Method A. A 250
mL round-bottom flask equipped with a magnetic stir bar, a nitrogen
inlet, and a condenser was charged with THF/H2O (5:1, 75 mL) and
degassed with nitrogen via gas dispersion frit for 20 min. The addition
of tosyl-cystamine (9) (7.60 g, 16.50 mmol) and triphenyl phosphine
(5.20 g, 19.83 mmol) followed, and the reaction was refluxed for 12 h
with a heating mantle. The solution was then cooled down to room
temperature, and degassed 2 M NaOH (17.4 mL, 34.80 mmol) was
added in one portion. The light pink solution was stirred at room
temperature for 5 min, 1,3-dibromopropane (0.76 mL, 7.43 mmol)
was added, and the solution was refluxed via a heating mantle for 12 h.
The reaction mixture was diluted with EtOAc (50 mL) and 1 M HCl
(40 mL), the aqueous layer was extracted with EtOAc (2 × 30 mL),
and the organic layers were combined, dried with sodium sulfate,
filtered, and concentrated in vacuo. The yellow residue was dissolved
in ethanol (200 mL) and warmed to 40 °C followed by the addition
of zinc chloride (11.24 g, 82.5 mmol) in ethanol (100 mL). The
ethanolic solution was stirred at 40 °C for 0.5 h, then cooled down to
room temperature, stirred for 3 h, and the cloudy solution was placed
in a 0 °C fridge for 12 h. The white Zn(TPPO)2Cl2 was filtered,
washed with cold ethanol (2 × 50 mL), the mother liquor
concentrated, and subjected to column chromatography (3:1 → 2:1
→ 1:1; Hex/EtOAc) affording 5 (3.44 g, 13.53 mmol) in an 82%
yield as a clear oil.
Method B. A 250 mL round-bottom flask equipped with a
magnetic stir bar, a nitrogen inlet, and a condenser was charged with
THF/H2O (5:1, 75 mL) and degassed with nitrogen via gas
dispersion frit for 20 min. The addition of tosyl-cystamine (7.60 g,
16.50 mmol), potassium carbonate (6.84 g, 49.50 mmol), and
dithiothreitol (DTT) (3.31 g, 21.45 mmol) followed, and the reaction
was refluxed with a heating mantle until the disappearance of a
starting material via TLC (∼1.5 h). The reaction was allowed to cool
down to room temperature followed by the dropwise addition of 1,3-
dibromopropane (1.85 mL, 18.15 mmol) over 15 min. The solution
was refluxed with a heating mantle a final time for 12 h, cooled down
to room temperature, and diluted with EtOAc (200 mL). The organic
layer was washed with 1 M HCl (2 × 20 mL), water (20 mL), and
brine (20 mL), dried with sodium sulfate, filtered, and concentrated in
vacuo. The residue was subjected to column chromatography (3:1 →
H
DOI: 10.1021/acs.joc.9b01682
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The Journal of Organic Chemistry
Article
1
2:1 → 1:1; Hex/EtOAc) to obtain 5 (6.72 g, 13.37 mmol) as a clear
viscous oil in an 81% yield.
145−148 °C. H NMR (400 MHz, chloroform-d) δ 7.73 (d, J = 8.3
Hz, 4H), 7.31 (d, J = 8.3 Hz, 4H), 4.83 (s, 2H), 3.02 (t, J = 6.1 Hz,
6H), 2.43 (s, 4H), 1.67 (p, J = 6.2 Hz, 2H); 13C{1H} NMR (101
MHz, chloroform-d) δ 143.6, 136.8, 129.8, 127.0, 39.7, 29.9, 21.5.
HRMS (ESI) m/z [M + H]+ calcd for C17H23O4N2S2 383.1094, found
383.1097.
Method C. A 250 mL round-bottom flask equipped with a
magnetic stir bar, a nitrogen inlet, and a condenser was charged with
THF/H2O (5:1, 75 mL) and degassed with nitrogen via gas
dispersion frit for 20 min. The addition of tosyl-cystamine (7.60 g,
16.50 mmol) and tributyl phosphine (4.89 mL, 19.83 mmol) was
followed, and the reaction was refluxed for 2 h via a heating mantle.
The solution was then cooled down to room temperature, and
degassed 2 M NaOH (17.4 mL, 34.80 mmol) was added in one
portion. The solution was stirred at room temperature for 5 min, 1,3-
dibromopropane (0.76 mL, 7.43 mmol) was added, and the solution
was refluxed for 12 h via a heating mantle. The reaction mixture was
diluted with EtOAc (150 mL), washed with 1 M HCl (2 × 20 mL),
water (20 mL), and brine (15 mL), dried with sodium sulfate, filtered,
concentrated in vacuo, and subjected to column chromatography (3:1
→ 1:1, Hex/EtOAc). Compound 5 (7.30 g, 14.52 mmol) was
obtained in an 88% yield as an opaque oil.
N,N′-(Propane-1,3-diyl)bis(N-(2-hydroxyethyl)-4-methyl-
benzenesulfonamide) (8a). Method A. A 25 mL round-bottom
flask equipped with a condenser, a nitrogen inlet, and a magnetic stir
bar was charged with N,N′-(propane-1,3-diyl)bis(4-methylbenzene-
sulfonamide) (7) (0.82 g, 2.14 mmol), potassium carbonate (0.65 g,
4.71 mmol), ethylene carbonate (0.75 g, 8.56 mmol), and DMF (0.5
M, 4.3 mL). This solution was maintained at 110−120 °C for 4 h in
an oil bath controlled with a thermocouple and then cooled to 23 °C.
The DMF was removed, and the yellow residue was taken up in ethyl
acetate (50 mL) and washed with 0.5 M HCl (10 mL), water (10
mL), and brine (10 mL). The organic layer was dried with sodium
sulfate, filtered, and concentrated in vacuo to afford a thick yellow oil.
The residue was subjected to column chromatography (2:1, ethyl
acetate/hexane) to afford 8a (0.473 g, 1.01 mmol) as a clear viscous
oil in a 47% yield.
Method B. A 50 mL round-bottom flask was charged with N,N′-
(propane-1,3-diyl)bis(4-methylbenzenesulfonamide) (7) (5.00 g, 13.1
mmol), ethylene carbonate (2.88 g, 32.8 mmol), and potassium
hydroxide (0.050 g, 0.891 mmol). The mixture was stirred for 4 h at
115 °C in an oil bath controlled with a thermocouple, at which time,
the residue was cooled to 0 °C via an external ice bath and diluted
with MilliQ water (10 mL). The solution was extracted with ethyl
acetate (20 mL × 3), and the combined organic layers were washed
with 1 M HCl (10 mL), water (10 mL), and brine (5 mL), dried with
sodium sulfate, filtered, and concentrated in vacuo. The remaining
residue was purified via flash chromatography (3:2 EtOAc/Hex)
providing 8a (5.47 g, 11.66 mmol) in an 89% yield as a clear oil. Rf =
0.40 (EtOAc); 1H NMR (400 MHz, chloroform-d) δ 7.63 (d, J = 8.4
Hz, 4H), 7.25 (d, J = 8.1 Hz, 4H), 3.74−3.64 (m, 4H), 3.42−3.33 (m,
4H), 3.20−3.09 (m, 8H), 2.35 (s, 6H), 1.90 (p, J = 7.4 Hz, 2H);
13C{1H} NMR (101 MHz, chloroform-d) δ 143.6, 135.5, 129.8,
Method D. A 500 mL two-neck round-bottom flask equipped with
a magnetic stir bar, a pressure-equalizing drop funnel, a condenser,
and a nitrogen inlet was charged with THF/H2O (5:1, 217 mL) and
degassed with nitrogen via gas dispersion frit for 20 min. At which
time, NaOH (0.95 g, 23.87 mmol) followed by TCEP·HCl (6.84 g,
23.87 mmol) was added, and the mixture was degassed with nitrogen
via gas dispersion frit for 10 min. Tosyl-cystamine (10.0 g, 21.7
mmol) was added in one portion, and the solution was refluxed with a
heating mantle until the disappearance of a starting material via TLC
(∼15 min). The solution was cooled down to room temperature, at
which time, nitrogen-degassed 2 M NaOH (54 mL, 27.00 mmol) was
added in one portion, and the pressure-equalizing drop funnel was
charged with 1,3-dibromopropane in nitrogen-degassed THF (10
mL). The solution was stirred at room temperature for 5 min followed
by the dropwise addition of 1,3-dibromopropane over 15 min and
refluxed with a heating mantle for 12 h. The reaction mixture was
diluted with EtOAc (300 mL), washed with 1 M HCl (2 × 30 mL),
water (30 mL), and brine (20 mL), dried with sodium sulfate, filtered,
concentrated in vacuo, and subjected to column chromatography (3:1
→ 1:1, Hex/EtOAc) to afford compound 5 (9.82 g, 19.53 mmol) in a
127.2, 61.4, 51.7, 47.9, 28.6, 21.5. IR νmax 3524, 2927, 1597, 1455,
1331, 1155, 1088, 815, 728, 656 cm−1; HRMS (ESI) m/z [M + H]+
calcd for C21H31O6N2S2 471.1618, found 471.1619.
1
90% yield as an opaque oil. Rf = 0.5 (Hex/EtOAc, 1:1). H NMR
(400 MHz, chloroform-d) δ 7.70 (d, J = 8.3 Hz, 4H), 7.25 (d, J = 8.2
Hz, 4H), 5.54−5.34 (m, 2H), 3.04 (t, J = 7.0 Hz, 4H), 2.52 (t, J = 6.8
Hz, 4H), 2.41 (t, J = 7.1 Hz, 8H), 2.36 (s, 6H), 1.65 (p, J = 7.1 Hz,
2H); 13C{1H} NMR (101 MHz, chloroform-d) δ 143.6, 136.8, 129.8,
127.0, 42.3, 31.6, 30.2, 28.9, 21.5. IR νmax 3277, 2921, 2256, 1597,
1494, 1409, 1321, 1185, 1092, 1019, 813 cm−1. HRMS (ESI) m/z [M
+ Na]+ calcd for C21H30O4N2NaS4 525.0981, found 525.0985.
2,2′-(Propane-1,3-diylbis(sulfanediyl))diacetyl Chloride (6).
A 50 mL flame-dried round-bottom flask equipped with a magnetic
stir bar, a condenser, and a calcium sulfate drying tube was charged
with 2,2′-(propane-1,3-diylbis(sulfanediyl))diacetic acid (2) (0.400 g,
1.78 mmol), methylene chloride (17.8 mL), and thionyl chloride
(0.320 mL, 1.78 mmol) in the indicated order. This mixture was
refluxed with an external heating mantle for 12 h and then
concentrated in vacuo. To the yellow oil, trituration from toluene
(3 × 10 mL) afforded the final bis-acid chloride 6 (0.428 g, 1.64
N-(2-Hydroxyethyl)-4-methyl-N-(3-((4-methylphenyl)-
sulfonamido)propyl)benzenesulfonamide (8b). A 50 mL round-
bottom flask was charged with N,N′-(propane-1,3-diyl)bis(4-methyl-
benzenesulfonamide) (7) (5.00 g, 13.1 mmol), ethylene carbonate
(2.88 g, 32.8 mmol), and potassium hydroxide (0.050 g, 0.891 mmol).
The mixture was stirred for 2 h at 110 °C in an oil bath controlled
with a thermocouple, at which time, the residue was cooled to 0 °C
via an external ice bath and diluted with MilliQ water (10 mL). The
solution was extracted with ethyl acetate (20 mL × 3), and the
combined organic layers were washed with 1 M HCl (10 mL), water
(10 mL), and brine (5 mL), dried with sodium sulfate, filtered, and
concentrated in vacuo. The remaining residue was purified via flash
chromatography (3:2 EtOAc/Hex) providing 8b (2.18 g, 5.11 mmol)
in a 39% yield as a clear oil. Rf = 0.50 (EtOAc); 1H NMR (400 MHz,
chloroform-d) δ 7.71 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H),
7.31−7.21 (m, 4H), 5.64 (t, J = 6.4 Hz, 1H), 3.68 (q, J = 5.3 Hz, 2H),
3.28−3.10 (m, 4H), 2.99 (q, J = 6.3 Hz, 2H), 2.83 (s, 1H), 2.39 (s,
3H), 2.38 (s, 3H), 1.77 (p, J = 6.5 Hz, 2H); 13C{1H} NMR (101
MHz, chloroform-d) δ 143.8, 143.3, 136.9, 135.3, 129.9, 129.7, 127.2,
127.0, 61.5, 51.8, 47.5, 39.9, 28.9, 21.5. IR νmax 3475, 3217, 2932,
2873, 1597, 1493, 1451, 1326, 1151, 1091, 741 cm−1. HRMS (ESI)
m/z [M + Na]+ calcd for C19H26O5N2NaS2 449.1175, found
449.1176.
1
mmol) in a 92% yield as a viscous light-yellow oil. H NMR (300
MHz, chloroform-d) δ 3.71 (s, 1H), 2.78 (t, J = 7.1 Hz, 1H), 1.93 (p,
J = 7.1 Hz, 1H); 13C{1H} NMR (75 MHz, chloroform-d) δ 170.2,
45.2, 31.2, 27.8.
N,N′-(Propane-1,3-diyl)bis(4-methylbenzenesulfonamide)
(7). A 500 mL round-bottom flask equipped with a magnetic stir bar
and a pressure-equalizing drop funnel was charged with water (80
mL) and potassium carbonate (13.82 g, 100.0 mmol) followed by 1,3-
propanediamine (4.2 mL, 50.0 mmol). The pressure-equalizing drop
funnel was charged with THF (85 mL) and para-toluenesulfonyl
chloride (19.06 g,100.0 mmol) and was added over a 4.5 h period to
the carbonate solution. Once added, the solution was stirred for 10 h
at 23 °C and poured over water (40 mL) at 0 °C. The white solid was
filtered, washed with ethanol (50.0 mL, 0 °C), and dried in vacuo to
afford bis-sulfonamide 7 (18.17 g, 47.50 mmol) in a 95% yield. Mp =
N-(2-(2-Hydroxyethoxy)ethyl)-N-(3-((N-(2-hydroxyethyl)-4-
methylphenyl)sulfonamido)propyl)-4-methylbenzenesulfo-
namide (8c). A 50 mL round-bottom flask was charged with N,N′-
(propane-1,3-diyl)bis(4-methylbenzenesulfonamide) (7) (5.00 g, 13.1
mmol), ethylene carbonate (2.88 g, 32.8 mmol), and potassium
hydroxide (0.050 g, 0.891 mmol). The mixture was stirred for 4 h at
190 °C in an oil bath controlled with a thermocouple, at which time,
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Article
the brownish residue was cooled to 0 °C via an external ice bath and
diluted with MilliQ water (10 mL). The solution was extracted with
ethyl acetate (20 mL × 3), and the combined organic layers were
washed with 1 M HCl (10 mL), water (10 mL), and brine (5 mL),
dried with sodium sulfate, filtered, and concentrated in vacuo. The
remaining residue was purified via flash chromatography (3:2,
EtOAc/Hex) providing N-(2-(2-hydroxyethoxy)ethyl)-N-(3-((N-(2-
hydroxyethyl)-4-methylphenyl)sulfonamido)propyl)-4-methylbenze-
nesulfonamide 8c (3.57 g, 6.94 mmol) in a 53% yield as a clear oil. Rf
= 0.35 (EtOAc); 1H NMR (400 MHz, chloroform-d) δ 7.60 (dd, J =
8.3, 2.5 Hz, 4H), 7.38−7.05 (m, 4H), 3.72−3.63 (m, 2H), 3.63−3.58
(m, 2H), 3.52 (t, J = 5.4 Hz, 2H), 3.45−3.38 (m, 2H), 3.24 (t, J = 5.4
Hz, 2H), 3.16 (dd, J = 8.4, 6.4 Hz, 2H), 3.14−3.04 (m, 4H), 2.33 (s,
6H), 1.86 (p, J = 7.4 Hz, 1H); 13C{1H} NMR (101 MHz, chloroform-
d) δ 143.5, 143.4, 136.2, 135.5, 129.8, 129.7, 127.2, 127.1, 72.4, 70.0,
61.4, 61.2, 51.5, 48.4, 48.0, 47.3, 28.2, 21.4. IR νmax 3516, 3411, 2926,
2875, 1597, 1328, 1151, 1087, 727 cm−1. HRMS (ESI) m/z [M +
Na]+ calcd for C22H30O8N2NaS2 537.1700, found 537.1699.
N,N′-Bis-(p-toluenesulfonyl)cystamine (9). A 300 mL round-
bottom flask equipped with a magnetic stir bar, a nitrogen inlet, and a
pressure-equalizing addition funnel was charged with cystamine (10.0
g, 44.0 mmol), potassium carbonate (24.32 g, 176.0 mmol), and
MilliQ water (70 mL). The addition funnel was charged with THF
(75 mL) and p-toluenesulfonyl chloride (16.77 g, 88.0 mmol) and
added dropwise over 2 h at room temperature. The mixture was
vigorously stirred for 12 h, at which time, the THF was evaporated in
vacuo, and the aqueous layer was diluted with 0.5 M HCl (50 mL)
and extracted with EtOAc (3 × 50 mL). The organic layer was
washed with 3 M HCl (2 × 20 mL), water (2 × 20 mL), and
saturated NaCl (1 × 20 mL), dried over Na2SO4, filtered, and
concentrated, providing a white solid. The crude product was
recrystallized from methanol to give N,N′-bis-(para-toluenesulfonyl)-
cystamine (19.0 g, 39.6 mmol) in a 90% yield as a white solid.
Consistency of spectral data is shown with the lit. data.28 Melting
point: 89−90 °C (lit. 77−78 °C)1; Rf = 0.10 (7:3, Hex/EtOAc); IR
νmax 3281, 2925, 2865, 1595, 1418, 1324, 1157, 1092, and 814, cm−1;
1H NMR (chloroform-d, 300 MHz): δ 7.77 (d, J = 8.4 Hz, 2H), 7.33
(d, J = 8.4 Hz, 2H), 4.96 (t, J = 6.4 Hz, 1H), 3.26 (q, J = 6.4 Hz, 2H),
2.73 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H); 13C{1H} NMR (chloroform-d,
75 MHz): δ 21.7, 38.0, 41.8, 127.2, 130.0, 136.8, 143.8.
1,11-Dithia-4,8-diazacyclotetradecane-4,8-diium Dichloride
(L1-HCl). A 25 mL round-bottom flask was charged with 1 M
HCl(MeOH) (3 mL), cooled to ∼0 °C via an external ice bath, and L1
(36.70 mg, 0.157 mmol) in MeOH (1 mL) was added. The solution
was warmed to room temperature and concentrated in vacuo
affording 1,11-dithia-4,8-diazacyclotetradecane-4,8-diium dichloride
1
(0.483 mg, 0.157 mmol) as a white residue in quantitative yield. H
NMR (400 MHz, deuterium oxide) δ 3.27 (t, J = 6.1 Hz, 4H), 3.23 (t,
J = 7.3 Hz, 4H), 2.86 (t, J = 6.1 Hz, 4H), 2.73 (t, J = 6.4 Hz, 4H),
2.16 (p, J = 7.3 Hz, 2H), 1.86 (p, J = 6.3 Hz, 2H); 13C{1H} NMR
(101 MHz, deuterium oxide) δ 44.1, 42.5, 29.5, 27.5, 26.3, 20.5;
HRMS (ESI) m/z [M−2HCl+H]+ calcd for C10H23N2S2 235.1279,
found 235.1298.
1,11-Dithia-4,8-diazacyclotetradecane Copper II Perchlo-
rate (L1Cu(ClO4)2). A 25 mL round-bottom flask equipped with a
magnetic stir bar, a nitrogen inlet, and rubber septa was charged with
MeCN (5 mL) and L1 (36.70 mg, 0.157 mmol) and cooled to ∼0 °C
via an external ice bath; in copper(II) perchlorate, MeCN (2 mL) was
added. The solution immediately turned a vibrant purple color and
was stirred at room temperature for an additional 30 min, followed by
concentration in vacuo. Chelate L1Cu(ClO4)2 was obtained as
purple prisms in quantitative yields. [(L1Cu)2μ-Cl](ClO4)3 was
isolated using an identical procedure but as a separate sample.
Caution! Perchlorate salts of metal complexes containing organic
ligands as solids or in organic solvents are potentially explosive.
Although no problems were encountered by us, cautious handling of
only small amounts of these compounds should be the rule.
3,3′-(Ethane-1,2-diylbis(sulfanediyl))dipropanenitrile (13).
A Pyrex test tube was charged with potassium carbonate (0.304 g,
2.20 mmol), 1,2-ethanedithiol (0.08 mL, 1.00 mmol), and
acrylonitrile (0.28 mL, 4.40 mmol). This solution was placed in a
sonication bath and sonicated for 30 min at 53 °C. After which,
chloroform (5 mL) was added, potassium carbonate was filtered off,
and the mother liquor was concentrated in vacuo to provide 0.197 g
(98%) of 3,3′-(ethane-1,2-diylbis(sulfanediyl))dipropanenitrile as a
white solid. 1H NMR (400 MHz, CDCl3) δ 2.83 (s, 2H), 2.82 (t, J =
7.0 Hz, 2H), 2.65 (t, J = 7.0 Hz, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 118.4, 32.2, 27.8, 19.1. IR νmax 2938, 2917, 2239, 1417,
1279, 1213, 901, 739 cm−1. HRMS (ESI) m/z [M + Na]+ calcd for
C8H12N2NaS2 223.0334, found 223.0335.
1,4-Dithia-8,11-diazacyclotetradecane Bis-hydrochloride
(L2-HCl). A 25 mL round-bottom flask equipped with a condenser,
a nitrogen inlet, and a magnetic stir bar was charged with 8,11-ditosyl-
1,4-dithia-8,11-diazacyclotetradecane (12) (0.200 g, 0.368 mmol) and
xylene (0.12 M, 3.1 mL). The solution was cooled to 0 °C, Red-Al
(3.5 M (toluene), 1.7 mL) was added dropwise, and the mixture was
refluxed with a heating mantle for 2 h and then cooled to 23 °C. The
solution was cooled to 0 °C, 3 M sodium hydroxide (4 mL) was
added dropwise, and the cloudy solution was extracted with
chloroform (5 × 15 mL). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated in vacuo to afford a
yellow residue. The crude product was treated with methanolic HCl
(1 M, 10 mL), concentrated to ∼1 mL, and filtered. The filter cake
was washed with cold methanol (1 mL) to provide L2-HCl (0.984 g,
0.320 mmol) as a white powder in an 87% yield. 1H NMR (400 MHz,
deuterium oxide) δ 4.65 (s, 4H), 3.51 (s, 4H), 3.28 (t, J = 7.3 Hz,
4H), 2.85 (s, 4H), 2.68 (t, J = 6.7 Hz, 4H), 1.98 (p, J = 6.9 Hz, 4H);
13C{1H} NMR (101 MHz, deuterium oxide) δ 47.7, 42.9, 33.7, 30.5,
1,11-Dithia-4,8-diazacyclotetradecane (L1). A flame-dried 100
mL round-bottom flask equipped with a septum, a magnetic stir bar,
and a nitrogen inlet was charged with small pieces of sodium metal
(41.4 mg, 1.80 mmol), freshly distilled dimethoxy ethane (2 mL), and
naphthalene (254.0 mg, 1.98 mmol). This mixture was stirred at room
temperature under a nitrogen atmosphere for 2 h, affording a dark
green solution. A second flame-dried round-bottom flask equipped
with a septum, a magnetic stir bar, and a nitrogen inlet was charged
with freshly distilled dimethoxy ethane (1 mL), and bis-sulfonamide 3
(100.0 mg, 0.180 mmol) was cooled to −30 °C via an external
acetone/liquid nitrogen bath. The sodium naphthalenide solution was
added dropwise using a gas-tight syringe to the round-bottom flask at
−30 °C, until the solution maintained the dark green color for 5 min.
The reaction was then allowed to warm to room temperature over 15
min and cooled to 0 °C via an external ice bath. At this time, water (1
mL) was added, which dissipated the green color immediately, and
the solution was concentrated in vacuo. The residue was treated with
3 M HCl (10.0 mL, pH ∼ 1) and washed with ethyl acetate (4 × 5
mL). The aqueous layer was then basified using 6 M NaOH (5.00
mL, pH ∼ 11) at 0 °C, and the freebase was extracted with
chloroform (5 × 5 mL), dried with sodium sulfate, filtered, and
concentrated in vacuo. The orange oil was then subjected to a
26.1. IR νmax 3381, 2935, 1616, 1455, 1015, 805 cm−1. HRMS (ESI)
m/z [M−2HCl+H]+ calcd for C10H23N2S2 235.1297, found 235.1298.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b01682.
■
b
Dowex50W-X12 (H+) column (methanol wash, eluted with 6 M
S
NH3(MeOH)) to afford L1 (36.70 mg, 0.157 mmol) as a clear oil in an
87% yield. 1H NMR (400 MHz, chloroform-d) δ 2.88−2.81 (m, 4H),
2.80−2.72 (m, 12H), 1.89 (p, J = 6.5 Hz, 2H), 1.82 (p, J = 5.8 Hz,
2H); 13C{1H} NMR (101 MHz, chloroform-d) δ 46.9, 46.8, 32.4,
29.0, 28.3, 27.2. IR νmax 3284, 2912, 2809, 1660, 1445, 1294, 1256,
1129, 742 cm−1. HRMS (ESI) m/z [M + H]+ calcd for C10H23N2S2
235.1297, found 235.1297.
1H, 13C, gCOSY, gHSQC, and gHMBC spectra,
including X-ray crystallography, and HRMS (PDF)
X-ray crystallographic data for compound 7 (CIF)
X-ray crystallographic data for compound 8b (CIF)
J
DOI: 10.1021/acs.joc.9b01682
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The Journal of Organic Chemistry
Article
Synthesis and characterization of the copper (II) complexes of new
N2S2-donor macrocyclic ligands: synthesis and in vivo evaluation of
the 64Cu complexes. Dalton Trans. 2009, 177−184. (b) Voss, S. D.;
Smith, S. V.; DiBartolo, N.; McIntosh, L. J.; Cyr, E. M.; Bonab, A. A.;
Dearling, J. L. J.; Carter, E. A.; Fischman, A. J.; Treves, S. T.; Gillies, S.
D.; Sargeson, A. M.; Huston, J. S.; Packard, A. B. Positron emission
tomography (PET) imaging of neuroblastoma and melanoma with
64Cu-SarAr immunoconjugates. Proc. Natl. Acad. Sci. U.S.A. 2007, 104,
17489−17493.
X-ray crystallographic data for compound 4 (CIF)
X-ray crystallographic data for compound 3 (CIF)
X-ray crystallographic data for compound 10 (CIF)
X-ray crystallographic data for compound L1-HCl (CIF)
X-ray crystallographic data for compound [(L1Cu)2μ-
Cl](ClO4)3 (CIF)
X-ray crystallographic data for compound L1Cu(ClO4)2
(CIF)
(6) (a) Tishchenko, K.; Beloglazkina, E.; Proskurnin, M.;
Malinnikov, V.; Guk, D.; Muratova, M.; Krasnovskaya, O.; Udina,
A.; Skvortsov, D.; Shafikov, R. R.; Ivanenkov, Y.; Aladinskiy, V.;
Sorokin, I.; Gromov, O.; Majouga, A.; Zyk, N. New copper (II)
thiohydantoin complexes: Synthesis, characterization, and assessment
of their interaction with bovine serum albumin and DNA. J. Inorg.
Biochem. 2017, 175, 190−197. (b) Goldenberg, D. M. Cancer Therapy
with Radiolabeled Antibodies; CRC Press, 2018.
(7) Kim, S.; Minier, M. A.; Loas, A.; Becker, S.; Wang, F.; Lippard, S.
Achieving Reversible Sensing of Nitroxyl by Tuning the Ligand
Environment of Azamacrocyclic Copper (II) Complexes. J. Am. Chem.
Soc. 2016, 138, 1804−1807.
AUTHOR INFORMATION
Corresponding Author
*E-mail: itaschne@iun.edu.
ORCID
Ian S. Taschner: 0000-0002-4210-9288
Tia L. Walker: 0000-0001-6499-7856
Christopher J. Ziegler: 0000-0002-0142-5161
■
Notes
The authors declare no competing financial interest.
(8) Walker, T. L.; Taschner, I. S.; Chandra, S. M.; Taschner, M. J.;
Engle, J. T.; Schrage, B. R.; Ziegler, C. J.; Gao, X.; Wheeler, S. E.
Lone-Pair-Induced Topicity Observed in Macrobicyclic Tetra-thia
Lactams and Cryptands: Synthesis, Spectral Identification, and
Computational Assessment. J. Org. Chem. 2018, 83, 10025−10036.
(9) (a) Rorahucher, D. B.; Martin, M. J.; Koenig Bauer, M.; Malik,
R. R.; Schroeder, J. F.; Ochrymowycz, L. A. Copper Coordination
Chemistry: Biochemical and Inorganic Perspectives; Karlin, K. D.;
Zubieta, J., Eds.; Academic Press: New York, 1983; p 167.
(b) Siegfried, L.; Kaden, T. A. Metal complexes with macrocyclic
ligands. Part XIX. Synthesis and Cu2+ complexes of a series of 12-, 14-,
and 16-membered cis-and trans-N2S2-macrocycles. Helv. Chim. Acta
1984, 67, 29.
ACKNOWLEDGMENTS
■
The authors thank the Ohio Board of Regents for funds used
to purchase the Bruker-Nonius Apex CCDC X-ray diffrac-
tometer and the National Science Foundation (CHE-
0840446). The authors thank the University of Notre Dame
Mass Spectrometry and Proteomics Facility, supported by NSF
grant CHE-0741793, for exact mass measurements on
compound 2 and Indiana University Bloomington Mass
Spectrometry Facility for exact mass measurements on all
additional compounds. This work was also supported by NIH
1R15 GM119074-01.
(10) (a) Bridger, G. J.; Skerlj, R. T.; Padmanabhan, S.; Martellucci,
S. A.; Henson, G. W.; Struyf, S.; Witvrouw, M.; Schols, D.; De Clercq,
E. Synthesis and structure-activity relationships of phenylenebis-
(methylene)-linked bis-azamacrocycles that inhibit HIV-1 and HIV-2
replication by antagonism of the chemokine receptor CXCR4. J. Med.
Chem. 1999, 42, 3971−3981. (b) Li, N.; Eberlein, C. M.; Volkert, W.
A.; Ochrymowycz, L.; Barnes, C.; Ketring, A. R. Comparisons of
105Rh(III) Chloride Complexation with [14]aneNS3, [14]aneN2S2
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(11) Walker, T. L.; Malasi, W.; Bhide, S.; Parter, T.; Zhang, D.;
Freedman, A.; Modarelli, J. M.; Engle, J. T.; Ziegler, C. J.; Custer, P.;
Youngs, W. J.; Taschner, M. J. Synthesis and characterization of 1,8-
dithia-4,11-diazacyclotetradecane. Tetrahedron Lett. 2012, 53, 6548−
6551.
ADDITIONAL NOTES
Potential nitrogen mustard derivative, use safe laboratory
practices when isolating the product.
If ammonium salts are present after ion-exchange chromatog-
raphy, dissolve the freebase in chloroform, filter, and
concentrate in vacuo to provide L1 free of salts.
■
a
b
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