Straightforward synthesis of novel biphenyl-based macrobicyclic azathioethers

Article abstract of DOI:10.1055/s-2007-990867

The synthesis and characterization of two new macrobicyclic azathioether ligands are reported. The biphenyl-based compounds were prepared by traditional organic reactions and cyclization methods. The identity of one compound was confirmed by X-ray crystallography. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990867

3706
PAPER
Straightforward Synthesis of Novel Biphenyl-Based Macrobicyclic
Azathioethers
S
ynthesis of Bip
h
henyl-Based
o
M
acrobicyc
m
lic
A
zathioether
s
as Gregor, Christian F. Weise, Vasile Lozan, Berthold Kersting*
Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax +49(341)9736199; E-mail: b.kersting@uni-leipzig.de
Received 11 June 2007
Herein we report efficient synthetic routes to the pro-
ligands L2 and L3 (Figure 2) containing 4-phenylthiophe-
nol and 4-tert-butylphenylthiophenol units in place of the
4-tert-butylthiophenol groups. Azathioether macrocycles
of this type have not been previously reported.
Abstract: The synthesis and characterization of two new macrobi-
cyclic azathioether ligands are reported. The biphenyl-based com-
pounds were prepared by traditional organic reactions and
cyclization methods. The identity of one compound was confirmed
by X-ray crystallography.
Key words: macrocycles, sulfur, nitrogen, biphenyl
N
N
S
N
N
S
N
There is currently much interest in the development of
supporting ligands that create confined environments
about active metal coordination sites.1 Motivations in this
area are diverse and include the stabilization of reactive
intermediates, the activation and transformation of small
molecules,2 and the construction of more effective en-
zyme mimics,3 to name a few.
R
R
N
L2 (R = H)
L3 (R = tBu)
Figure 2 Azathioether macrocycle pro-ligands L2 and L3
We are interested in the coordination chemistry of the
hexaazadithiophenolate macrocycle H2L1 and have re-
cently reported on the coordinating properties of this
ligand system towards various divalent and trivalent tran-
sition metal ions.4,5 The N6S2 macrocycle forms bioctahe-
dral [L1M2(L¢)]n+ complexes (Figure 1) with bowl-shaped
binding cavities. The unique reactivity features of these
complexes6 led us to investigate potential routes to deriv-
atives of H2L1 which would provide more rigid and deeper
binding cavities.
Schemes 1 and 2 depict the synthetic procedures. The
synthesis of the new macrocycles commenced with the
Suzuki coupling of commercially available 1-halo-3,5-
dimethylbenzenes 17 with the corresponding phenylbo-
ronic acids 28 in the presence of [(Ph3P)4Pd] and Na2CO3
to furnish the biaryls 3 in good yields (>85%).9–12 The
subsequent bromination can be carried out catalyzed by
iron in CCl4 in the dark or alternatively with KBrO3/HBr
in acetic acid.13 In both cases, the reaction took place pref-
erentially at the 4-position providing the monobromides 4
(75%) as colorless needles after recrystallization from
CHCl3–EtOH.14 In the synthesis of 4b, the dibromo deriv-
ative 5 was observed as a by-product.15
tBu
L'
N
N
M
N
N
Some time ago we discovered that 4-tert-butyl-2,6-di-
methylbromobenzene can be converted to 2-bromo-5-
tert-butylbenzene-1,3-dialdehyde by oxidation with chro-
mium(VI) oxide in acetic anhydride.16 We reasoned that a
similar protocol could be applied for the synthesis of the
dialdehydes 7. However, the bromides 4 failed to react in
this fashion. Therefore, an alternative protocol involving
bromination with NBS/AIBN and subsequent hydrolysis
of the resulting dibromomethylbromobenzenes 6 with
AgNO3 was employed.17–20 This sequence provided large
quantities of the pure aldehydes 7 in moderate to good
yields (Scheme 1). The compounds can be easily purified
by recrystallization.
M
N
S
S
N
N
SH
SH
N
N
N
N
[L1M2(L')]n+
N
tBu
H2L1
Figure 1 Macrocycle H2L1 and the structure of its bioctahedral
complexes [L1M2(L¢)]n+
Conversion of the dialdehydes 7 to the tetraldehydes 8
was accomplished by treatment with ethanedithiol in
DMF in the presence of K2CO3 in analogy to a published
procedure (Scheme 2).5 The macrocycles 9 were prepared
SYNTHESIS 2007, No. 23, pp 3706–3712
Advanced online publication: 31.10.2007
DOI: 10.1055/s-2007-990867; Art ID: Z14307SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7

PAPER
Synthesis of Biphenyl-Based Macrobicyclic Azathioethers
3707
R
tBu
R
R
2a (R = H)
2b (R = tBu)
Br2, cat. Fe,
CCl4, 0 °C
Hal
B(OH)2
Br
(or KBrO3, HBr
HOAc, 0 °C)
[Pd(PPh3)4], Na2CO3
Br
Br
1a (Hal = Br)
1b (Hal = I)
3a (R = H)
3b (R = tBu)
4a (R = H)
4b (R = tBu)
5
R
R
NBS, CCl4
AgNO3
hν
(MeCN)
Br
Br
O
Br
O
Br
Br
Br
7a (R = H)
7b (R = tBu)
6a (R = H)
6b (R = tBu)
Scheme 1 Synthesis of the dialdehydes 7
by a [2+1] condensation reaction of tetraaldehydes 8 with An attractive feature of 9 compared to unprotected thiols
two equivalents of diethylenetriamine in EtOH–CH2Cl2 is that its secondary amines can be readily functionalized
using medium-dilution conditions followed by reduction without affecting the thioether moieties. Thus, reductive
with NaBH4. The yields of the new macrobicycles are ex- methylation of 9 with formaldehyde and formic acid un-
cellent (>90%). The remarkable selectivity for the [2+1] der Eschweiler–Clarke conditions gave the permethylated
condensation products is likely due to the template effect macrocycles L2 and L3 in nearly quantitative yield. All
of the bridging ethylene unit which predisposes the four compounds were identified by various spectroscopic
aldehyde groups in the correct position.21–23
methods. The molecular structure of L3 was further con-
firmed by an X-ray crystal structure determination of a
R
O
O
HS
SH
S
R
R
S
K2CO3, DMF
O
O
8a (R = H)
8b (R = tBu)
N
1.
H
NH2
NH2
O
Br
O
NaBH4
2.
7a (R = H)
7b (R = tBu)
N
R'
R'N
S
NR'
S
R
R
R'N
NR'
R'
N
9a (R, R' = H)
9b (R = tBu, R' =H )
HCHO, HCO2H
L2 (R = H, R' = Me)
L3 (R = tBu, R' = Me )
Scheme 2
Synthesis 2007, No. 23, 3706–3712 © Thieme Stuttgart · New York

3708
T. Gregor et al.
PAPER
(vw), 850 (s), 761 (vs), 738 (w), 689 (vs), 670 (vw), 647 (vw), 610
(vw), 585 (m), 541 (vw), 504 (vw), 437 cm–1 (vw).
tems in which there is little conjugation between the two 1H NMR (400 MHz, CDCl3): d = 2.26 (s, 6 H, CH3), 6.88 (s, 1 H,
suitable crystal (Figure 3). The torsional angle between
the Ar moieties is 35(2)°, a typical value for biphenyl sys-
aromatic rings.24 The conformation of the macrocycle is
ArH), 7.13 (s, 2 H, ArH), 7.20 (t, J = 7.2 Hz, 1 H, ArH), 7.30 (t,
J = 7.4 Hz, 2 H, ArH), 7.49 (d, J = 7.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 21.8, 125.8, 127.7, 127.8, 129.2,
129.6, 138.7, 141.6, 141.8.
otherwise very similar to that of L1.25
FAB-MS: m/z = 182.1 ([M]+).
Anal. Calcd for C14H14: C, 92.26; H, 7.74. Found: C, 92.21; H, 7.78.
4-Bromo-3,5-dimethylbiphenyl (4a)
Method A: To a solution of 3,5-dimethylbiphenyl (3a; 13.9 g, 76.3
mmol) in CCl4 (150 mL) was added iron powder (427 mg, 10
mol%). A solution of Br2 (12.2 g, 76.3 mmol) in CCl4 (150 mL) was
added dropwise at 0 °C in the dark during a period of 6 h. The mix-
ture was stirred for further 20 h at r.t. and filtered off from the iron
catalyst. The solution was washed with sat. aq NaHSO3 (3 × 100
mL), 2 M aq NaOH (3 × 100 mL), and H2O (3 × 100 mL), and dried
(MgSO4). Evaporation of the solvent under reduced pressure gave
crude 4a as a colorless oil, which crystallized on standing. Recrys-
tallization from EtOH gave analytically pure material (15.02 g,
75%); colorless needles; mp 70 °C.
Method B: To a solution of 3,5-dimethylbiphenyl (3a; 34.22 g,
187.7 mmol), iron powder (1.05 g, 18.8 mmol, 10 mol%), and
Figure 3 Molecular structure of L3. The ellipsoids represent a
probability of 50%. H atoms are omitted for clarity.
KBrO3 (10.45 g, 62.50 mmol) in AcOH (130 mL) was slowly added
48% aq HBr (37.6 mL, 325.9 mmol) dropwise at r.t. in the dark. Af-
ter stirring for further 4 h, the mixture was poured onto ice-water
(1.2 L) with good stirring. The solid residue was filtered, washed
with aq NaHSO3 and H2O. Recrystallization from EtOH gave ana-
lytically pure 4a (37.92 g, 77%); colorless needles. The analytical
data were identical with those of the compound obtained by Method
A.
In conclusion, a convenient and facile synthetic procedure
for the preparation of macrobicyclic amine-thioethers
containing biphenyl head groups has been described. The
protocols are feasible on a multi-gram scale. Removal of
the sulfur protecting groups will be the subject of future IR (KBr): 3449 (vw), 3032 (vw), 2982 (vw), 2916 (vw), 1958 (vw),
1889 (vw), 1752 (vw), 1597 (vw), 1570 (w), 1497 (vw), 1462 (s),
work.
1436 (m), 1380 (w), 1337 (vw), 1312 (vw), 1263 (vw), 1156 (vw),
1095 (w), 1077 (w), 1029 (s), 1014 (m), 1001 (w), 874 (m), 826
[(Ph3P)4Pd] was prepared as described in the literature.26 1-Bromo-
(vw), 766 (vs), 697 (s), 603 (vw), 567 (w), 546 (w), 468 (w), 419
cm–1 (vw).
3,5-dimethylbenzene (1a), 1-iodo-3,5-dimethylbenzene (1b) and
phenylboronic acid (2a) were purchased from commercial vendors.
Melting points (uncorrected): Barnstead Electrothermal IA9100 ap-
paratus. IR spectra: PerkinElmer FT-IR System 2000 spectrometer.
1H NMR and 13C NMR spectra: Bruker Advance DRX-400 spec-
trometer. 1H and 13C chemical shifts are reported in ppm downfield
from internal tetramethylsilane or residual solvent peaks as internal
standards. Elemental analysis: Vario EL elemental analyzer. Chro-
matography: Merck Kieselgel 60 (0.040–0.063 mm). Mass spectra:
Finnigan Mat 8230 (EI, 70 eV), Waters ZAB-HSQ instrument
(FAB, fast atom bombardment); Bruker-Daltronics FT-ICR (ESI+,
electrospray ionization mass spectra).
1H NMR (400 MHz, CDCl3): d = 2.44 (s, 6 H, CH3), 7.25 (s, 2 H,
ArH), 7.30 (t, J = 7.3 Hz, 1 H, ArH), 7.39 (t, J = 7.4 Hz, 2 H, ArH),
7.51 (d, J = 7.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 24.5, 127.2, 127.4, 127.5, 127.8,
129.2, 139.0, 140.2, 140.8.
FAB-MS: m/z = 260.0 ([M]+, C14H1379Br), 262.0 ([M]+,
C14H1381Br).
Anal. Calcd for C14H13Br: C, 64.39; H, 5.02. Found: C, 64.30; H,
5.04.
3,5-Bis(dibromomethyl)-4-bromobiphenyl (6a)
3,5-Dimethylbiphenyl (3a)11
A solution of 4-bromo-3,5-dimethylbiphenyl (4a; 4.62 g, 17.7
mmol), NBS (18.89 g, 106.1 mmol), and AIBN (174.4 mg, 1.06
mmol) in CCl4 (150 mL) under argon was heated at reflux and irra-
diated with an external tungsten lamp (50 W). After 48 h, further
portions of NBS (1.89 g, 10.6 mmol) and AIBN (17.4 mg, 0.106
mmol) dissolved in CCl4 (15 mL) were carefully added, and the re-
action continued for another 20 h. After cooling to r.t., the precipi-
tated succinimide and unreacted NBS were removed by filtration.
The filtrate was diluted with EtOH (30 mL), and concentrated under
reduced pressure to afford the crude product as a microcrystalline
solid. Recrystallization from CH2Cl2–EtOH (1:1) gave pure 6a
(9.22 g, 90%); colorless needles; mp 172 °C.
To a solution of 1-bromo-3,5-dimethylbenzene (1a; 24.00 g, 129.7
mmol), phenylboronic acid (2a; 17.40 g, 142.7 mmol), and
[(Ph3P)4Pd] (4.50 g, 3.89 mmol) in toluene (250 mL) was added a
solution of Na2CO3 (27.50 g, 259.5 mmol) in H2O (100 mL) under
argon. The resulting mixture was heated under reflux for 72 h. After
cooling to r.t., the organic phase was separated, and the aqueous
phase extracted with CH2Cl2 (3 × 30 mL). Concentration of the
combined organic phases produced a brown oil, which was purified
by column chromatography on a column of silica gel (eluent: n-hex-
ane–EtOAc, 10:1) to provide 2 (20.67 g, 87%); colorless oil.
IR (KBr): 3082 (w), 3060 (w), 3031 (m), 2918 (m), 2859 (w), 2732
(vw), 1946 (vw), 1878 (vw), 1803 (vw), 1741 (vw), 1676 (vw),
1604 (s), 1577 (w), 1497 (w), 1467 (m), 1377 (vw), 1332 (vw), 1263
(vw), 1181 (vw), 1156 (vw), 1075 (w), 1033 (w), 913 (vw), 893
IR (KBr): 3432 (w), 3016 (vw), 2964 (vw), 1635 (vw), 1432 (m),
1398 (vw), 1319 (vw), 1259 (vw), 1213 (m), 1141 (m), 1122 (w),
Synthesis 2007, No. 23, 3706–3712 © Thieme Stuttgart · New York

PAPER
Synthesis of Biphenyl-Based Macrobicyclic Azathioethers
3709
1089 (w), 1079 (w), 1033 (w), 1019 (w), 1000 (vw), 977 (w), 889
(m), 870 (vw), 825 (vw), 766 (vs), 732 (vs), 696 (vs), 659 (w), 638
(m), 570 (s), 548 (w), 520 (s), 494 (vw), 460 (vw), 412 cm–1 (vw).
1H NMR (400 MHz, CDCl3): d = 7.17 (s, 2 H, ArCH), 7.46 (t,
J = 7.4 Hz, 1 H, ArH), 7.53 (t, J = 7.4 Hz, 2 H, ArH), 7.67 (dd,
J = 7.1 Hz, J = 1.3 Hz, 2 H, ArH), 8.24 (s, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 39.2, 127.0, 128.6, 129.1, 131.0,
138.3, 141.0, 141.0, 142.3.
FAB-MS: m/z = 575.5 ([M]+, C14H9Br5).
Macrobicyclic Amine-Thioether 9a
Solutions of tetraaldehyde 8a (2.20 g, 4.31 mmol) in CH2Cl2 (200
mL) and of diethylenetriamine (887.3 mg, 8.60 mmol) in EtOH
(200 mL) were added simultaneously over a period of 6 h to a mix-
ture of CH2Cl2 (450 mL) and EtOH (150 mL). After complete addi-
tion, the mixture was stirred at r.t. for 18 h. The CH2Cl2 was then
removed at reduced pressure and a solution of NaBH4 (1.30 g, 34.4
mmol) in EtOH (100 mL) was added. After stirring at r.t. for 2 h, the
mixture was acidified with concd HCl to pH 1 and evaporated to
dryness. H2O (100 mL) and CH2Cl2 (300 mL) were added to the res-
idue, the pH of the aqueous phase was adjusted to 13 with 3 M aq
KOH and the heterogeneous mixture was stirred vigorously for 1 h.
The layers were separated and the aqueous phase was extracted with
CH2Cl2 (3 × 80 mL). The combined organic fractions were dried
(Na2SO4) and the solvent evaporated to provide crude 9a as a yel-
lowish foamy solid (1.75 g, 62%). This compound was used for the
next step without further purification.
Anal. Calcd for C14H9Br5: C, 29.16; H, 1.57. Found: C, 29.07; H
1.49.
4-Bromo-3,5-diformylbiphenyl (7a)
To an argon-purged solution of 6a (8.0 g, 13.9 mmol) in MeCN
(180 mL) was added a solution of AgNO3 (11.78 g, 69.30 mmol) in
H2O (70 mL). The mixture was heated at reflux under argon in the
dark for 2 h. The resulting suspension was cooled to r.t., and the pale
yellow AgBr was filtered off. The filtrate was concentrated in vac-
uum to give a beige solid, which was extracted with CH2Cl2 (3 × 60
mL). The organic phases were combined, washed with H2O (3 × 50
mL), dried (Na2SO4), and evaporated to dryness to give crude 7a.
Recrystallization from CH2Cl2–C6H12 (1:1) gave pure 7a (3.43 g,
86%); colorless needles; mp 133 °C.
IR (KBr): 3430 (m), 3056 (w), 2921 (m), 2819 (m), 1686 (m), 1635
(w), 1594 (w), 1554 (vw), 1497 (vw), 1434 (m), 1402 (w), 1373 (w),
1335 (vw), 1260 (w), 1197 (w), 1108 (s), 1040 (m), 890 (w), 803
(vw), 762 (vs), 697 (vs), 620 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 1.8–2.0 (br s, 6 H, NH), 2.89 (s, 8
H, NCH2), 2.96 (s, 8 H, NCH2), 3.27 (s, 4 H, SCH2), 4.02 (s, 8 H,
ArCH2), 7.34 (t, J = 7.3 Hz, 2 H, ArH), 7.42 (t, J = 7.3 Hz, 4 H,
ArH), 7.52 (s, 4 H, ArH), 7.59 (dd, J = 7.3 Hz, 4 H, ArH).
IR (KBr): 3442 (w), 3046 (w), 2907 (vw), 2867 (vw), 1953 (vw),
1690 (vs), 1582 (w), 1561 (m), 1496 (vw), 1452 (m), 1437 (m),
1400 (m), 1384 (s), 1313 (vw), 1279 (vw), 1233 (s), 1193 (m), 1122
(vw), 1094 (w), 1022 (w), 999 (vw), 953 (s), 927 (w), 906 (w), 891
(vw), 841 (vw), 806 (vw), 763 (s), 709 (m), 695 (s), 596 (vw), 520
(m), 499 (vw), 409 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 7.44 (t, J = 7.3 Hz, 1 H, ArCH),
7.50 (t, J = 7.3 Hz, 2 H, ArH), 7.65 (d, J = 7.3 Hz, 2 H, ArH), 8.37
(s, 2 H, ArH), 10.58 (s, 2 H, CHO).
ESI-MS (CHCl3–MeOH): m/z = 653.4 ([M + H]+).
Methylated Macrobicyclic Amine-Thioether L2
An aq solution of formaldehyde (37%, 16 mL) was added dropwise
at r.t. to a solution of the macrobicyclic thioether 9a (1.35 g, 10.0
mmol) in 99% formic acid (19 mL). The mixture was heated under
reflux for 12 h, and then concentrated under reduced pressure to 10
mL. After H2O (50 mL) and CH2Cl2 (100 mL) had been added to the
sticky residue, the aqueous solution was made basic (pH 13) with 3
M aq NaOH and the heterogeneous mixture was stirred vigorously
for 30 min. The layers were separated and the aqueous phase was
extracted with CH2Cl2 (3 × 100 mL). The combined organic frac-
tions were dried (K2CO3) and filtered. MeOH (100 mL) was added
to the clear filtrate. On evaporation of the CH2Cl2 under reduced
pressure, the permethylated macrocycle L2 precipitated as a fine-
grained colorless solid (702 mg, 46%); mp 189 °C. Attempts to ob-
tain an analytically pure material were not successful. Nevertheless,
the spectroscopic data provide sufficient evidence for the formula-
tion of L2.
13C NMR (100 MHz, CDCl3): d = 122.8, 126.7, 127.8, 130.0, 130.2,
135.7, 140.0, 143.6, 193.1.
EI-MS: m/z = 288.8 ([M]+).
Anal. Calcd for C14H9BrO2: C, 58.16; H, 3.14. Found: C, 57.99; H
3.04.
Tetraaldehyde 8a
To a suspension of anhyd K2CO3 (718 mg, 5.20 mmol) in DMF (15
mL) was added under argon 1,2-ethanedithiol (163 mg, 1.73 mmol),
followed by 4-bromo-3,5-diformylbiphenyl (7a; 1.00 g, 3.46
mmol). The crimson-red mixture was stirred at 50 °C for 3 days to
give a yellow suspension. H2O (60 mL) was added dropwise to af-
ford the crude product as an impure yellow solid, which was collect-
ed by filtration and dried in air. Concentration of a solution of 8a in
CH2Cl2–C6H12 under reduced pressure yielded pure 8a (787 mg,
91%); colorless needles; mp 239 °C.
IR (KBr): 3443 (w), 3057 (w), 3030 (vw), 2945 (s), 2837 (s), 2780
(vs), 1595 (m), 1555 (vw), 1498 (w), 1454 (s), 1399 (w), 1354 (m),
1298 (m), 1196 (m), 1110 (s), 1075 (m), 1042 (s), 1027 (s), 933
(vw), 893 (m), 862 (w), 842 (vw), 812 (vw), 763 (vs), 697 (s), 620
(w), 596 (vw), 552 (vw), 473 cm–1 (vw).
1H NMR (400 MHz, CDCl3): d = 2.05 (s, 12 H, NCH3), 2.29 (s, 6
H, NCH3), 2.63 (s, 16 H, NCH2), 3.19 (s, 4 H, SCH2), 3.88 (s, 8 H,
ArCH2), 7.33 (t, J = 7.3 Hz, 2 H, ArH), 7.42 (t, J = 7.3 Hz, 4 H,
ArH), 7.53 (s, 4 H, ArH), 7.56 (dd, J = 7.3 Hz, 4 H, ArH).
IR (KBr): 3427 (w), 3062 (w), 2864 (vw), 1689 (vs), 1583 (vw),
1549 (vw), 1500 (vw), 1451 (w), 1436 (w), 1399 (w), 1377 (m),
1304 (vw), 1284 (vw), 1237 (m), 1208 (vw), 1186 (vw), 1105 (vw),
1041 (vw), 1001 (vw), 950 (m), 922 (vw), 902 (w), 842 (vw), 763
(m), 731 (w), 698 (w), 660 (vw), 603 (vw), 520 (w), 499 (vw), 430
cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 2.98 (s, 4 H, CH2), 7.45 (t, J = 7.3
Hz, 2 H, ArH), 7.50 (t, J = 7.3 Hz, 2 H, ArH), 7.65 (dd, J = 7.3 Hz,
4 H, ArH), 8.35 (s, 4 H, ArH), 10.78 (s, 4 H, CHO).
13C NMR (100 MHz, CDCl3): d = 37.5, 42.4, 42.5, 55.8, 56.3, 61.9,
127.1 127.2, 127.7, 128.6, 133.2 140.3, 140.6, 145.1.
ESI-MS (CHCl3–MeOH): m/z = 737.4 ([M + H]+).
4¢-tert-Butyl-3,5-dimethylbiphenyl (3b)12
The same procedure as for the preparation of 3a was used. To an ar-
gon-purged solution of 1-iodo-3,5-dimethylbenzene (1b; 9.33 g,
40.2 mmol), 4-tert-butylphenylboronic acid (2b; 7.88 g, 44.3
mmol), and [(Ph3P)4Pd] (1.39 g, 1.20 mmol) in toluene (200 ml)
was added under argon a solution of Na2CO3 (8.52 g, 80.4 mmol) in
H2O (50 mL), and the resulting mixture was heated under reflux for
72 h. After cooling to r.t., the organic phase was separated, and the
13C NMR (100 MHz, CDCl3): d = 38.5, 127.0, 128.9, 129.2, 132.2,
137.6, 138.0, 138.9, 143.0, 190.6.
ESI-MS (CHCl3–MeOH): m/z = 533.1 ([M + Na]+).
Anal. Calcd for C30H22O4S2: C, 70.56; H, 4.34. Found: C, 70.36; H
4.24.
Synthesis 2007, No. 23, 3706–3712 © Thieme Stuttgart · New York

3710
T. Gregor et al.
PAPER
aqueous phase extracted with CH2Cl2 (3 × 50 mL). Concentration
of the combined organic phases produced a brown oil, which was
purified by column chromatography on a column of silica gel (elu-
ent: n-hexane) to provide 3b (20.67 g, 95%); colorless oil; Rf = 0.46
(n-hexane).
FAB-MS: m/z (%) = 631.7 ([M]+, C18H1779Br5), 552.8 ([M – Br]+),
473.8 ([M – 79Br – 79Br]+).
Anal. Calcd for C18H17Br5: C, 34.16; H, 2.17. Found: C, 34.05; H
2.30.
1H NMR (400 MHz, CDCl3): d = 1.37 (s, 9 H, CH3), 2.38 (s, 6 H,
ArCH3), 6.98 (s, 1 H, ArH), 7.21 (s, 2 H, ArH), 7.44 (d, J = 8.1 Hz,
2 H, ArH), 7.51 (d, J = 8.1 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 22.1, 32.1, 35.2, 125.7, 126.3,
127.7, 129.4, 138.8, 139.3, 141.8, 150.7.
4-Bromo-4¢-tert-butyl-3,5-diformylbiphenyl (7b)
The preparation of this compound was similar to that used for dial-
dehyde 7a. To an argon-purged solution of 6b (3.60 g, 6.00 mmol)
in THF (100 mL) was added a solution of AgNO3 (5.61 g, 33.0
mmol) in H2O (45 mL). The mixture was heated at reflux under ar-
gon in the dark for 24 h. The resulting suspension was cooled to r.t.,
and the pale yellow AgBr was filtered off. The organic layer was
separated and the filtrate extracted with CH2Cl2 (3 × 15 mL). The
organic phases were combined, dried (Na2SO4), and evaporated un-
der vacuum to give a viscous oil, which was purified by column
chromatography on a column of silica gel (eluent: EtOAc–n-hexane
1:10) to provide 7b (911 mg, 44%); white powder; Rf = 0.31
(EtOAc–n-hexane 1:10); mp 109–110 °C.
ESI-MS: m/z = 238.0 ([M]+), 223 ([M – CH3]+).
4-Bromo-4¢-tert-butyl-3,5-dimethylbiphenyl (4b)14
The preparation of this compound was analogous to that of 4a. To a
solution of 3b (9.10 g, 38.2 mmol) in CCl4 (150 mL) was added iron
powder (212 mg, 3.80 mmol). To this suspension was added a solu-
tion of Br2 (6.72 g, 42.1 mmol) in CCl4 (150 mL) dropwise at 0 °C
in the dark over 8 h. The mixture was stirred for further 12 h at r.t.,
then washed with sat. aq NaHSO3 (3 × 100 mL), extracted with
CH2Cl2 (3 × 100 mL), and the combined organic phases were dried
(MgSO4). Evaporation of the solvent under reduced pressure gave
crude 4b, which was purified by recrystallization from i-PrOH; col-
orless needles (8.46 g, 70%); mp 72–73 °C; Rf = 0.56 (n-hexane).
IR (KBr): 3056 (w), 2961 (m), 2867 (w), 1691 (s), 1556 (w), 1461
(w), 1439 (w), 1418 (w), 1385 (m), 1363 (w), 1308 (w), 1264 (w),
1232 (m), 1193 (w), 1112 (w), 1091 (w), 1021 (m), 944 (m), 910
(w), 832 (m), 702 (w), 599 (w), 556 (w), 512 (w), 440 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 1.38 (s, 9 H, CH3), 7.51 (d, J = 8.4
Hz, 2 H, ArCH), 7.59 (d, J = 8.4 Hz, 2 H, ArH), 8.35 (s, 2 H, ArH),
10.56 (s, 2 H, CHO).
IR (KBr): 3031 (w), 2981 (s), 2903 (m), 2866 (m), 1910 (w), 1581
(w), 1557 (w), 1515 (w), 1452 (s), 1383 (m), 1362 (m), 1308 (m),
1235 (w), 1115 (m), 1029 (s), 1011 (m), 878 (w), 831 (s), 743 (w),
705 (w), 604 (w), 569 (m), 521 cm–1 (w).
13C NMR (100 MHz, CDCl3): d = 31.24, 34.71, 126.22, 126.59,
128.89, 133.0, 134.35, 134.65, 141.26, 152.25, 190.69.
1H NMR (400 MHz, CDCl3): d = 1.38 (s, 9 H, CH3), 2.49 (s, 6 H,
ArCH3), 7.30 (s, 2 H, ArH), 7.46 (d, J = 8.4 Hz, 2 H, ArH), 7.51 (d,
J = 8.4 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 24.7, 32.0, 35.2, 126.4, 127.1,
127.3, 127.5, 138.1, 139.2, 140.3, 151.1.
ESI-MS: m/z = 399.0 ([M + MeOH + Na]+).
Anal. Calcd for C18H17BrO2: C, 62.62; H, 4.96. Found: C, 62.54; H,
5.02.
Tetraaldehyde 8b
The same procedure as for the preparation of 8a was used. To a sus-
pension of anhyd K2CO3 (207 mg, 1.50 mmol) in DMF (15 mL) was
added under argon 1,2-ethanedithiol (47 mg, 0.50 mmol), followed
by dialdehyde 7b (345 mg, 1.00 mmol). The crimson-red mixture
was stirred at 50 °C for 72 h to give a yellow suspension. H2O (80
mL) was added dropwise to afford the crude product as an impure
yellow solid, which was collected by filtration and dried in air. Con-
centration of a solution of dry 8b in CH2Cl2–C6H12 under reduced
pressure provided colorless needles (278 mg, 89%); mp 247 °C.
FAB-MS: m/z (%) = 316.1 ([M]+, C18H2179Br), 318.1 ([M]+,
C18H2181Br).
Anal. Calcd for C18H21Br: C, 68.14; H, 6.67. Found: C, 68.22; H
6.56.
3,5-Bis(dibromomethyl)-4-bromo-4¢-tert-butylbiphenyl (6b)
The same procedure as for the preparation of 6a was used. A solu-
tion of bromide 5b (6.00 g, 18.91 mmol), NBS (20.20 g, 113.5
mmol), and AIBN (186 mg, 1.13 mmol) in CCl4 (400 mL) was heat-
ed under argon at reflux and irradiated with an external tungsten
lamp (50 W). After 6 h, further portions of NBS (2.00 g, 11.23
mmol) and AIBN (50 mg, 0.30 mmol) dissolved in CCl4 (15 mL)
were carefully added, and the reaction continued for another 12 h.
After cooling to r.t., the precipitate of succinimide and unreacted
NBS were removed by filtration. The filtrate was diluted with EtOH
(30 mL), and concentrated under reduced pressure to afford the
crude product as a microcrystalline solid. Recrystallization from
EtOH provided 6b (8.74 g, 73%); yellow-brown needles; mp 158–
159 °C; Rf = 0.37 (n-hexane).
IR (KBr): 3354 (w), 3054 (m), 2959 (vs), 2931 (sh), 2903 (m), 2867
(m), 1683 (vs), 1613 (w), 1592 (w), 1568 (w), 1544 (m), 1519 (m),
1463 (m), 1439 (m), 1419 (s), 1393 (m), 1377 (s), 1363 (m), 1321
(w), 1304 (w), 1268 (m), 1246 (s), 1235 (s), 1209 (m), 1192 (s),
1133 (w), 1115 (m), 1037 (w), 1017 (m), 956 (s), 943 (m), 911 (s),
832 (vs), 744 (m), 713 (m), 703 (m), 687 (w), 605 (w), 559 (m), 545
(m), 519 (m), 474 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 1.38 (s, 18 H, CH3), 2.98 (s, 4 H,
CH2), 7.51 (d, J = 7.2 Hz, 4 H, ArH), 7.60 (d, J = 7.2 Hz, 4 H, ArH),
8.34 (s, 4 H, ArH), 10.78 (s, 4 H, CHO).
IR (KBr): 3022 (m), 2962 (s), 2901 (m), 2865 (m), 1909 (w), 1794
(w), 1663 (w), 1610 (w), 1595 (w), 1514 (w), 1473 (w), 1459 (m),
1429 (s), 1392 (m), 1362 (m), 1329 (w), 1307 (w), 1269 (m), 1248
(w), 1201 (m), 1147 (s), 1115 (m), 1020 (s), 974 (s), 894 (w), 831
(s), 747 (m), 734 (s), 705 (m), 655 (s), 635 (s), 585 (s), 568 (s), 547
(s), 432 (w), 414 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 1.38 (s, 9 H, CH3), 7.16 (s, 2 H,
ArCH), 7.54 (d, J = 8.4 Hz, 2 H, ArH), 7.60 (d, J = 8.4 Hz, 2 H,
ArH), 8.23 (s, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 31.3, 34.7, 38.5, 126.2, 126.8,
132.5, 134.6, 138.7, 138.9, 142.9, 152.3, 190.8.
Anal. Calcd for C38H38O4S2: C, 73.28; H, 6.15. Found: C, 73.22; H
6.14.
Macrobicyclic Amine-Thioether 9b
This compound was prepared in analogy to macrocycle 9a. Solu-
tions of tetraaldehyde 8b (187 mg, 0.300 mmol) in CH2Cl2 (50 mL)
and of diethylenetriamine (62 mg, 0.60 mmol) in EtOH (50 mL)
were added simultaneously over a period of 6 h to a mixture of
CH2Cl2 (90 mL) and EtOH (30 mL). After complete addition, the
mixture was stirred at r.t. for 18 h. The CH2Cl2 was then removed at
13C NMR (100 MHz, CDCl3): d = 31.3, 34.7, 39.4, 126.2, 126.8,
130.9, 135.5, 140.9, 142.3, 151.9 (one 13C signal was not observed).
Synthesis 2007, No. 23, 3706–3712 © Thieme Stuttgart · New York

PAPER
Synthesis of Biphenyl-Based Macrobicyclic Azathioethers
3711
reduced pressure and a solution of NaBH4 (91 mg, 2.40 mmol) in
EtOH (50 mL) was added. After stirring at r.t. for 2 h, the mixture
was acidified with concd HCl to pH 1 and evaporated to dryness.
H2O (50 mL) and CH2Cl2 (300 mL) were added to the residue, the
pH of the aqueous phase was adjusted to 13 with 3 M aq KOH and
the heterogeneous mixture was stirred vigorously for 30 min. The
layers were separated and the aqueous phase was extracted with
CH2Cl2 (4 × 50 mL). The combined organic fractions were dried
(Na2SO4) and the solvent evaporated to provided the crude 9b as a
yellowish foamy solid (215 mg, 92%); mp 252 °C. This compound
was used for the next step without further purification.
higher symmetry.29 Drawings were produced with Ortep-3.30 H at-
oms were placed at calculated positions and refined as riding atoms
with isotropic displacement parameters. All nonhydrogen atoms
were refined anisotropically.
Crystallographic Data31 for L3
C52H76N6S2 (Mr = 849.31 g/mol); crystal size 0.30 × 0.10 × 0.10
mm3; monoclinic, space group P21/c, a = 18.1380(2) Å,
b = 22.3510(3) Å, c = 12.9700(2) Å, b = 103.63(2)°, V = 5110.0(1)
Å, Z = 4, rcalcd = 1.104 g/cm3, m(Mo Ka) = 0.143 mm–1, qlimits 1.97–
26.02°. From a total of 40585 reflections, 9560 were unique
(Rint = 0.0604) and 4361 observed (I ≥ 2s(I). Final residuals:
R1 = 0.0595, wR2 = 0.1462 (I ≥ 2s(I)); 541 parameters, largest dif-
ference peak/hole = 0.668/0.356 e/Å3.
IR (KBr): 3299 (m), 3029 (w), 2961 (vs), 2928 (s), 2903 (m), 2858
(m), 2827 (m), 1597 (vw), 1463 (m), 1441 (m), 1429 (m), 1389 (w),
1377 (w), 1362 (w), 1334 (w), 1328 (w), 1312 (w), 1261 (vs), 1230
(vw), 1198 (w), 1182 (w), 1099 (vs), 1023 (vs), 802 (vs), 566 (m),
525 (w), 481 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 1.29 (s, 18 H, t-C4H9), 1.67 (br s,
6 H, NH), 2.80 (br s, 8 H, NCH2), 2.87 (s, 8 H, NCH2), 3.20 (s, 4 H,
SCH2), 3.94 (s, 8 H, ArCH2), 7.38 (d, J = 8.3 Hz, 4 H, ArH), 7.43
(s, 4 H, ArH), 7.46 (d, J = 8.3 Hz, 4 H, ArH).
References
(1) (a) Canary, J. W.; Gibb, B. C. Prog. Inorg. Chem. 1997, 45,
1. (b) Wieser, C.; Dieleman, C. B.; Matt, D. Coord. Chem.
Rev. 1997, 165, 93. (c) Hecht, S.; Fréchet, J. M. J. Angew.
Chem. Int. Ed. 2001, 40, 74; Angew. Chem. 2001, 113, 76.
(2) (a) Reetz, M. T.; Waldvogel, S. R. Angew. Chem. Int. Ed.
Engl. 1997, 36, 865; Angew. Chem. 1997, 109, 870.
(b) Reetz, M. T. Catal. Today 1998, 42, 399.
13C NMR (100 MHz, CDCl3): d = 31.3, 34.5, 37.0, 49.1, 49.8, 53.4,
125.6, 126.7, 128.6, 131.6, 137.0, 141.5, 145.1, 150.7.
ESI-MS: m/z = 765.4 ([M + H]+).
(c) Engeldinger, E.; Armspach, D.; Matt, D. Angew. Chem.
Int Ed. 2001, 40, 2526; Angew. Chem. 2001, 113, 2594.
(d) Slagt, V. F.; Reek, J. N. H.; Kramer, P. C. J.; van
Leeuwen, P. W. N. M. Angew. Chem. Int. Ed. 2001, 40,
4271; Angew. Chem. 2001, 113, 4401. (e) Yoshizawa, M.;
Takeyama, Y.; Kusukawa, T.; Fujita, M. Angew. Chem. Int.
Ed. 2002, 41, 1347; Angew. Chem. 2002, 114, 1403.
(f) Ooi, T.; Kondo, Y.; Maruoka, K. Angew. Chem. Int. Ed.
1998, 37, 3039; Angew. Chem. 1998, 110, 3213.
(3) (a) Blanchard, S.; Le Clainche, L.; Rager, M.-N.; Chansou,
B.; Tuchagues, J.-P.; Duprat, A. F.; Le Mest, Y.; Reinaud, O.
Angew. Chem., Int. Ed. Engl. 1998, 37, 2732; Angew. Chem.
1998, 110, 2861. (b) Rondelez, Y.; Bertho, G.; Reinaud, O.
Angew. Chem. Int. Ed. 2002, 41, 1044; Angew. Chem. 2002,
114, 1086. (c) Rondelez, Y.; Rager, M.-N.; Duprat, A.;
Reinaud, O. J. Am. Chem. Soc. 2002, 124, 1334.
(4) (a) Kersting, B.; Steinfeld, G. Chem. Commun. 2001, 1376.
(b) Kersting, B.; Steinfeld, G. Inorg. Chem. 2002, 41, 1140.
(5) Klingele, M. H.; Steinfeld, G.; Kersting, B. Z. Naturforsch.
2001, 56b, 901.
Methylated Macrobicyclic Amine-Thioether (L3)
The same procedure as for the preparation of L2 was used. The mac-
robicycle 9b (195 mg, 0.25 mmol) was dissolved in formic acid
(99%, 10 mL). To the warm solution was added an aq solution of
formaldehyde (37%, 10 mL). The mixture was heated under reflux
for 12 h, then concentrated in vacuo to 2–3 mL. H2O (30 mL) and
CH2Cl2 (50 mL) were added to the sticky residue, the pH of the
aqueous phase was adjusted to 13 by the addition of 3 M aq KOH,
and the heterogeneous mixture was stirred vigorously for 30 min.
The layers were separated and the aqueous phase was extracted with
CH2Cl2 (3 × 50 mL). The combined organic fractions were dried
(K2CO3) and filtered. MeOH (50 mL) was added to the clear solu-
tion. On evaporation of the CH2Cl2, the permethylated macrocycle
L3 was obtained as colorless crystals; yield: 178 mg (82%); mp
192–193 °C.
IR (KBr): 3053 (w), 3028 (w), 2962 (vs), 2905 (w), 2869 (w), 2833
(w), 2789 (s), 1743 (w), 1594 (w), 1548 (vw), 1514 (w), 1453 (m),
1416 (m), 1392 (m), 1365 (m), 1319 (m), 1298 (m), 1287 (m), 1262
(s), 1235 (w), 1213 (w), 1200 (w), 1167 (w), 1095 (vs), 1025 (vs),
986 (w), 971 (w), 928 (w), 894 (vw), 877 (vw), 866 (vw), 832 (vw),
800 (vs), 764 (m), 681 (m), 662 (m), 604 (m), 566 (s), 552 (m), 528
(m), 447 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 1.28 (s, 18 H, t-C4H9), 1.96 (s, 12
H, NCH3), 2.21 (s, 6 H, NCH3), 2.55 (s, 16 H, NCH2), 3.11 (s, 4 H,
SCH2), 3.79 (s, 8 H, ArCH2), 7.37 (d, J = 8.4 Hz, 4 H, ArH), 7.43
(d, J = 8.4 Hz, 4 H, ArH), 7.44 (s, 4 H, ArH).
(6) (a) Kersting, B. Angew. Chem. Int. Ed. 2001, 40, 3987;
Angew. Chem. 2001, 113, 4109. (b) Steinfeld, G.; Lozan,
V.; Kersting, B. Angew. Chem. Int. Ed. 2003, 42, 2261;
Angew. Chem. 2003, 115, 2363. (c) Käss, S.; Gregor, T.;
Kersting, B. Angew. Chem. Int. Ed. 2006, 45, 101; Angew.
Chem. 2006, 118, 107.
(7) Akiyama, R.; Kobayashi, S. Angew. Chem. Int. Ed. 2001, 40,
3469; Angew. Chem. 2001, 113, 3577.
13C NMR (100 MHz, CDCl3): d = 31.7, 34.5, 37.8, 42.2, 42.6, 55.9,
(8) Schmid, M.; Eberhardt, R.; Kukral, J.; Rieger, B. Z.
Naturforsch. 2002, 57b, 1141.
56.5, 62.0, 125.6, 126.8, 127.7, 133.0, 137.9, 140.1, 145.2, 150.3.
(9) (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun.
1981, 11, 513. (b) Old, D. W.; Wolfe, J. P.; Buchwald, S. L.
J. Am. Chem. Soc. 1998, 120, 9722.
(10) Bei, X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.;
Petersen, J. L. J. Org. Chem. 1999, 64, 6797.
ESI-MS: m/z = 849.5 ([M + H]+), 425.3 ([M + 2 H]2+).
Anal. Calcd for C52H76N6S2: C, 73.54; H, 9.02. Found: C, 73.23; H,
9.12.
(11) Liang, L.-C.; Chien, P.-S.; Huang, M.-H. Organometallics
Collection and Reduction of X-ray Data for 10
Single crystals of L3 were grown by slow evaporation of a MeCN–
EtOH solution. The data set was collected at 213(2) K using a STOE
IPDS-2T diffractometer and graphite monochromated Mo-Ka radi-
ation (0.71073 Å). The intensity data were processed with the pro-
gram STOE X-AREA. The structure was solved by direct methods27
and refined by full-matrix least-squares on the basis of all data
against F2 using SHELXL-97.28 PLATON was used to search for
2005, 24, 353.
(12) Cho, C.-H.; Park, H.; Park, M.-A.; Ryoo, T.-Y.; Lee, Y.-S.;
Park, K. Eur. J. Org. Chem. 2005, 3177.
(13) Sykes, P. Reaktionsmechanismen der Organischen Chemie;
VCH: Weinheim, 1988, 159–160.
(14) Monguchi, K.; Itoh, T.; Hirai, K.; Tomioka, H. J. Am. Chem.
Soc. 2004, 126, 11900.
Synthesis 2007, No. 23, 3706–3712 © Thieme Stuttgart · New York

3712
T. Gregor et al.
PAPER
(25) Siedle, G.; Kersting, B. Z. Anorg. Allg. Chem. 2003, 629,
(15) Preliminary analytical data for 5: Mp 76 °C. 1H NMR (400
MHz, CDCl3): d = 1.36 (s, 9 H, CH3), 2.39 (s, 3 H, CH3),
2.72 (s, 3 H, CH3), 7.07 (s, 1 H, ArH), 7.27 (d, J = 8.0 Hz, 2
H, ArH), 7.42 (d, J = 8.0 Hz, 2 H, ArH).
(16) Klingele, M. H.; Kersting, B. Z. Naturforsch. 2001, 56b,
437.
(17) Bankston, D. Synthesis 2004, 283.
(18) Harvey, R. G.; Dai, Q.; Ran, C.; Penning, T. M. J. Org.
Chem. 2004, 69, 2024.
2083.
(26) (a) Tellier, F.; Sauvetre, R.; Normant, J.-F. J. Organomet.
Chem. 1985, 292, 19. (b) Trost, B.; Mignami, K. J. Org.
Chem. 1986, 51, 3435.
(27) Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467.
(28) Sheldrick, G. M. SHELXL-97, Computer Program for
Crystal Structure Refinement; University of Göttingen:
Göttingen, 1997.
(19) Sander, W.; Exner, M.; Winkler, M.; Balster, A.; Hjerpe, A.;
Kraka, E.; Cremer, D. J. Am. Chem. Soc. 2002, 124, 13072.
(20) Josel, H. P.; Puff, H.; Franken, S.; Weber, E. J. Org. Chem.
1985, 50, 3125.
(21) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(22) Templated Organic Synthesis; Diederich, F.; Stang, P. J.,
Eds.; Wiley-VCH: Weinheim, 2000.
(29) Spek, A. L. PLATON - A Multipurpose Crystallographic
Tool; Utrecht University: Utrecht, 2000.
(30) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
(31) CCDC 648984 contains the supplementary crystallographic
data for compound L3. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html or
from the Cambridge Crystallgraphic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336033;
E-mail: deposit@ccdc.cam.ac.uk.
(23) Busch, D. H.; Stephenson, N. A. Coord. Chem. Rev. 1990,
100, 119.
(24) Bonstra, E. G. Acta. Crystallogr. 1963, 16, 816.
Synthesis 2007, No. 23, 3706–3712 © Thieme Stuttgart · New York