Click [3+2]-cycloaddition approach to novel Cookson's birdcage-derived thiacrown ethers

Article abstract of DOI:10.1055/s-0033-1338490

The synthesis of novel Cookson's birdcage-annulated thiacrowns as well as noncage oligomers with an incorporated 1,2,3-triazole moiety are described. The title compounds were prepared applying a click alkyne-azide cycloaddition reaction in the final macrocyclization step. Using this methodology a series of oligomers containing oxygen, nitrogen, and sulfur were prepared. The effective cycloaddition process was carried out under nonaqueous conditions in the presence of a catalytic amount of copper(I) iodide and N,N- diisopropylethylamine; the yields of oligomers were moderate to good. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338490

PAPER
▌2245
paper
‘
Click’ [3+2]-Cycloaddition Approach to Novel Cookson’s Birdcage-Derived
Thiacrown Ethers
Novel Cookson’s Birdcage-Derived Thiacrown Ethers
Monika Stefaniak, Marcin Jasiński, Jarosław Romański*
University of Łódź, Department of Organic and Applied Chemistry, Tamka 12, 91-403 Łódź, Poland
Fax +48(42)6655162; E-mail: romanski@uni.lodz.pl
Received: 05.03.2013; Accepted after revision: 09.05.2013
Abstract: The synthesis of novel Cookson’s birdcage-annulated
thiacrowns as well as noncage oligomers with an incorporated
1,2,3-triazole moiety are described. The title compounds were pre-
O
pared applying a click alkyne–azide cycloaddition reaction in the fi-
nal macrocyclization step. Using this methodology a series of
oligomers containing oxygen, nitrogen, and sulfur were prepared.
The effective cycloaddition process was carried out under nonaque-
ous conditions in the presence of a catalytic amount of copper(I) io-
dide and N,N-diisopropylethylamine; the yields of oligomers were
moderate to good.
X = O, n = 0–3
X = S, n = 1
O
O
X
X
n
X = NR, n = 2
1
O
2
Figure 1 Key building block Cookson’s diketone 1 and selected
known birdcage-derived crown ethers 2
Key words: macrocycles, thiacrown ethers, click chemistry, 1,3-
dipolar cycloaddition, cage compounds
8
for the construction of crown and lariat ethers, to the best
of our knowledge no reports on sulfur-containing ana-
logues have been published to date. Hence, we describe
the synthesis of some novel thiacrowns exploiting the
Huisgen–Sharpless–Meldal methodology of copper(I)-
1
Since the first synthesis of a thiacrown ether in 1934, sul-
fur-containing macrocycles have become one of the most
important tools in coordination chemistry, including in-
dustrial utility. A series of publications dealing with, for
9
catalyzed [3+2]-cycloaddition reaction.
example, polymeric, luminescent, chemosensory, and dye The model substrates, two diazido ethers 3a and 3b, were
2
materials illustrate more recent interest in this area. De- selected and prepared following literature protocols
1
0
spite their structural diversity, thiacrown ethers function- (Scheme 1). Thus, commercially available di- and trieth-
alized by simple, highly lipophilic moieties, e.g. terpene- ylene glycols were converted into the corresponding bis-
3
derived building blocks, still represent a rare class of tosylated derivatives. Subsequent substitution employing
macrocyclic compounds. Several reports exploiting sodium azide in N,N-dimethylformamide afforded the de-
4
Cookson’s diketone 1 for the preparation of chiral and sired materials in nearly quantitative yield. Taking into
achiral hydrocarbon-enriched crown ethers such as 2 were account the potentially explosive character of compounds
5
11
published by Marchand and co-workers (Figure 1). As such as 3 (the ‘rule of six’ ), the syntheses were per-
the annular oxygen present in the pentacycloundecane formed on a small scales (ca. 1–2 mmol), and the freshly
(
PCU) derivatives of type 2 can participate in metal ion prepared crude diazides 3 were used in the next step with-
complexation, the starting polycyclic ketone is an ideal out storage and further handling.
candidate for a rigid subunit in a macrocyclic ether.
As shown on Scheme 1, the α,ω-bispropargylated oxa-po-
In the search for stable and biocompatible silver(I) ion dands 4a,b were prepared using aforementioned ethylene
complexing agents, and also for other metals, we turned glycols and propargyl bromide in the presence of a cata-
6
7
our attention to 1,2,3-triazole as a readily available link- lytic amount of potassium iodide according to known
1
2
age. Although the click protocol has already been applied methodology. An analogous procedure was utilized,
1
2
. TsCl, NaOH
. NaN3, DMF
Br
O
X
O
n
HO
X
OH
N3
O
N3
n
n
NaH, KI
3
3
a (n = 1)
b (n = 2)
X = O or S
n = 1 or 2
4a (X = O, n = 1)
4b (X = O, n = 2)
5
5
a (X = S, n = 1)
b (X = S, n = 2)
Scheme 1 Synthesis of model podands functionalized with azido and propargyl groups
SYNTHESIS 2013, 45, 2245–2250
Advanced online publication: 18.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338490; Art ID: SS-2013-N0175-OP
Georg Thieme Verlag Stuttgart · New York
©

2246
M. Stefaniak et al.
PAPER
1
.
MgBr
HBr
NaN3
DMF
2
. PTSA, MgSO4
CH2Cl2
(PhCOO)2
O
O
O
O
O
1
6
Br
Br
N3
N3
7
8
Scheme 2 Synthesis of birdcage-derived diazide 8
starting with sulfur-containing diols, to provide hitherto the target 9a was isolated in a satisfactory 78% yield as a
unknown compounds 5a and 5b in high yield (85% and pale yellow oil. Analogously, the podands 3b and 4b bear-
7
7%, respectively).
Similarly, the lipophilic birdcage-derived building block
was obtained by halogen–azide exchange under suitable
ing elongated oxo-polyethylene bridges were examined
under the same reaction conditions affording the desired
macrocycle 9b in only 36% yield. Apparently, in contrast
to 9a, under aqueous conditions 26-membered crown-like
ether 9b was found only in traces by H NMR determina-
tion.
8
reaction conditions. As depicted in Scheme 2, the desired,
fairly stable, material 8 was prepared in four steps, start-
ing with Cookson’s diketone 1, and it was isolated in an
1
acceptable overall yield of 36%. After double addition of Next, with new podands 5a,b in hand, a series of four vari-
the Grignard reagent onto 1, the crude endo-endo-diol was ably linked sulfur-containing crowns 10a–d were pre-
1
3
dehydrated by a slightly modified literature protocol,
pared under nonaqueous reaction conditions (Scheme 3).
and the resulting divinyl derivative 6 was smoothly con- In contrast to the exceptionally high yield of 9a (78%), the
verted into the respective dibromide 7.14 As expected, a combination of diazide 3a and 5a furnished monosulfurat-
strong and broad absorption band, attributed to the azide ed analogue 10a in an acceptable 35% yield only. It
moieties, was found at 2079 cm–1 in the IR spectrum of should also be emphasized, that in all cases the isolated
newly prepared 8.
products of type 9 and 10 were contaminated with small
amounts (below 5%) of double-sized macromolecules.
Attempted separations by either standard column or pre-
parative thin-layer chromatography were unsuccessful.
First experiments on the alkyne–azide macrocyclization
reactions using model diazide 3a and bispropargyl ether
4a were carried out in the presence of copper sulfate and
sodium ascorbate as a source of Cu(I), in aqueous metha- Finally, the birdcage-derived diazide 8 and the bispropar-
nol. The very slow addition of 3a/4a (1:1) to the reaction gylated podands 5a,b were used as reaction partners in an
mixture under argon was found to be decisive for the for- analogous protocol (Scheme 4). The reaction of 5a with 8
mation of the macrocycle 9a. However, in all attempts the provided, along with the expected 11a (48%), significant
yield of the desired material was only moderate; the best amounts of double-sized macrocycles of type 12a (ap-
1
result gave 9a in 27% yield. As expected, in the H NMR prox. 20%) as a mixture of meso- and d,l-isomers. Unfor-
spectrum of 9a the sharp singlet attributed to the C(5)–H tunately, none of the major components of the crude
of the 1,2,3-triazole ring was found at δ = 7.49. In the mixture could be isolated in a pure state based on standard
quest for a more efficient protocol, the reaction was re- chromatography techniques. We assume that higher pref-
peated under nonaqueous conditions (dry acetonitrile) in erence for the formation of byproduct 12a is driven by ste-
the presence of catalytic amounts of copper(I) iodide/N,N- ric reasons (very likely due to rigidity of the cage-derived
diisopropylethylamine at slightly elevated temperatures substrate). This limitation was overcome by running the
(40 °C) as depicted in Scheme 3. After standard workup, reaction under two times higher dilution and prolonging
O
X
O
n
O
S
n
n
4
5
a,b (X = O)
a,b (X = S)
O
O
O
O
a or b
b
+
N
N
X = O
X = S
N
N
N
N
N
N
5–78%
N
N
N
N
35–50%
N3
O
m
N3
O
O
m
m
3
a,b
9
9
a (m = 1; n = 1)
b (m = 2; n = 2)
1
1
1
1
0a (m = 1; n = 1)
0b (m = 2; n = 1)
0c (m = 1; n = 2)
0d (m = 2; n = 2)
Scheme 3 Preparation of the 1,2,3-triazole-functionalized macrocycles of type 9 and 10. Reagents and conditions: (a) CuSO , sodium ascor-
4
bate, H O–MeOH (2:1), 65 °C, 24 h; (b) CuI, DIPEA, MeCN, 40 °C, 24 h.
2
Synthesis 2013, 45, 2245–2250
© Georg Thieme Verlag Stuttgart · New York

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Novel Cookson’s Birdcage-Derived Thiacrown Ethers
2247
O
N
N
N
N
O
S
O
CuI, DIPEA
+
n
N
O
N
MeCN, 40 °C
N3
N3
O
O
8
5a,b
S
n
1
1
1a (n = 1)
1b (n = 2)
S
S
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
N
N
N
N
N
N
N
N
N
O
O
O
O
S
meso-12a
S
d,l-12a
Scheme 4 Preparation of birdcage-derived macrocycles 11 and 12
the reaction time (48 h). Thus the target macrocycle 11a ments previous reports. Additionally, two exemplary
was isolated in very high yield (76%) and purity (>96%). macrocycles 11a,b functionalized with highly lipophilic
1
In the H NMR spectrum of 11a the diagnostic AB-system pentacycloundecane moiety were synthesized in high
peaks attributed to the methylene bridge of the PCU cage yields and purities starting with birdcage-derived diazide
were found at δ = 1.59 and 1.94 (J = 10.8 Hz, each). Two 8 and two novel propargylic thioether derivatives 5a and
characteristic singlets of the –CH O– group and the C(4)– 5b. The macrocyclic systems presented herein are of cur-
2
H of the 1,2,3-triazole ring were found at δ = 4.69 and rent interest to us with respect to their potential complex-
7.71, respectively. A similar result was found for bis-thia ing properties towards silver(I) and other heavy metal
cage-derived analogue 11b, but in this case the amount of ions.
larger-sized molecules was very low (under general con-
ditions).
Ethylene glycols, NaN , vinylmagnesium bromide, propargyl bro-
3
The syntheses of coronands are based on either inter- or mide, and other common reagents are commercially available. Di-
4
intramolecular processes.15 Although the latter approach
is more convenient for thermodynamic reasons, it usually
requires multistep preparation of properly (bi/poly)func-
tionalized substrates. On the other hand, in the alternative
ketone 1 was prepared according to a known procedure. Diazides
3
1
0
12
a,b and bis(propargyl) ethers 4a,b were prepared following lit-
erature protocols. NMR spectra were recorded with Bruker (Avance
III 600) instruments in CDCl ; chemical shifts reported relative to
3
1
13
solvent residual peak (
H: δ = 7.26 [CDCl3]; C: δ = 77.0 [CDCl ]).
3
intermolecular condensations the formation of complex IR spectra were measured with a Nexus FT-IR spectrophotometer.
HRMS and elemental analyses were recorded in the analytical lab-
oratories of Polish Academy of Sciences with a Finnigan MAT 95
mixtures of linear and macrocyclic products are observed.
For this reason, the template-directed or high dilution
strategies furnishing preferentially the desired oligomeric
systems are employed. More recently, the iterative syn-
(EI, FAB) or MaldiSYNAPT G2-S HDMS (ESI) instrument and
Vario EL III instrument, respectively.
thetic method based on the intramolecular azide–alkyne Bis(propargyl) Sulfides 5; General Procedure
To a soln of the corresponding glycol (0.01 mol) in anhyd THF
47.0 mL), NaH (60% in mineral oil, 1.23 g, 0.03 mol) was added
[
3+2]-cycloaddition protocol leading to a series of crown
(
8
b
ethers of C -axial symmetry has been described. The
2
at 0 °C under vigorous stirring. When the evolution of H had
ceased, a soln of propargyl bromide (6.0 mL of 80% wt in toluene,
2
synthesis of topologically isomeric crown-like ethers 9a,b
as well as their partially sulfurated analogues 10a–d via 8.01 g, 0.054 mol) and then solid KI (5 mg) were added. The mix-
the intermolecular route presented in this paper supple- ture was stirred overnight at r.t., the precipitate was filtered off, and
the solvent was removed under reduced pressure. The crude mixture
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2245–2250

2248
M. Stefaniak et al.
PAPER
was purified chromatographically (silica gel, hexanes–EtOAc, 8:2)
to yield 5 as yellow oils.
Macrocycles 9a,b, 10a–d, 11a,b, and 12a; General Procedure
under Nonaqueous Conditions
To a soln of CuI (6 mg, 0.032 mmol) and DIPEA (0.2 mL, 148 mg,
1.15 mmol) in anhyd, degassed MeCN (50 mL), a soln of diazide
and propargyl derivative in MeCN (50 mL) was added dropwise
over 6 h at 40 °C, under an argon atmosphere. The resulting mixture
was stirred at this temperature for a further 24 h and cooled to r.t.;
the mixture was extracted with CH Cl (2 × 40 mL). The combined
4
,10-Dioxa-7-thiatrideca-1,12-diyne (5a)
Yellow oil; yield: 1.4 g (85%).
–
1
IR (film): 3289, 2922, 2857, 2116, 1443, 1096 cm .
1
H NMR (600 MHz, CDCl ): δ = 2.45 (t, J = 2.4 Hz, 2 H), 2.79 (t,
3
2
2
J = 6.7 Hz, 4 H), 3.72 (t, J = 6.7 Hz, 4 H), 4.18 (d, J = 2.4 Hz, 4 H).
organic layers were dried (MgSO ) and filtered, and the solvents
4
13
C NMR (150 MHz, CDCl ): δ = 31.7, 58.1, 69.6, 74.7, 79.6.
were removed. The residue was purified by filtration through a sil-
3
ica gel pad (EtOAc, then 5% MeOH–CH Cl ).
2
2
Anal. Calcd for C H O S: C, 60.58; H, 7.12. Found: C, 60.26; H,
1
0
14
2
6.98.
Macrocycle 9a (m = 1, n = 1)
Diazide 3a (0.32 mmol) and propargyl derivative 4a (0.32 mmol)
gave macrocycle 9a (m = 1, n = 1). Pale yellow oil; yield: 85 mg
4
,13-Dioxa-7,10-dithiahexadeca-1,15-diyne (5b)
Yellow oil; yield: 2.2 g (77%).
(
78%).
–
1
IR (film): 3287, 2920, 2856, 2115, 1442, 1096 cm .
IR (KBr): 3135, 2947, 2903, 2863, 1470, 1356, 1220, 1147, 1053
1
–1
H NMR (600 MHz, CDCl ): δ = 2.45 (t, J = 2.4 Hz, 2 H), 2.75 (t,
cm .
3
J = 6.7 Hz, 4 H), 2.78 (s, 4 H), 3.69 (t, J = 6.7 Hz, 4 H), 4.18 (d,
J = 2.4 Hz, 4 H).
1
H NMR (600 MHz, CDCl ): δ = 3.74–3.75 (m, 4 H), 3.77–3.78 (m,
3
4
H), 3.86 (t, J = 4.8 Hz, 4 H), 4.52 (t, J = 4.8 Hz, 4 H), 4.78 (s, 4
13
C NMR (150 MHz, CDCl ): δ = 31.4, 32.6, 58.1, 69.6, 74.8, 79.5.
H), 7.49 (s, 2 H).
3
1
3
Anal. Calcd for C H O S : C, 55.78; H, 7.02. Found: C, 55.84; H,
C NMR (150 MHz, CDCl ): δ = 50.3, 64.9, 69.5, 69.8, 70.9,
3
12
18
2
2
6.85.
123.4, 145.6.
+
HRMS (FAB): m/z [M + H] calcd for C H N O : 339.1781;
found: 339.1777.
Cage Diazide 8
14 23
6
4
14
The dibromo cage derivative 7 (748 mg, 2 mmol) was dissolved in
anhyd DMF (5 mL). To this soln NaN (234 mg, 3.6 mmol) was
3
Macrocycle 9b (m = 2, n = 2)
Diazide 3b (0.25 mmol) and propargyl derivative 4b (0.25 mmol)
gave macrocycle 9b (m = 2, n = 2). Pale yellow oil; yield: 41 mg
added in small portions under an argon atmosphere. The mixture
was stirred 24 h at r.t. After this time, 50% aq NaOH (176 mg) was
added and stirring was continued for an additional 0.5 h. The mix-
ture was washed with 2% NaHCO soln and extracted with CH Cl
(
36%).
3
2
2
–
1
(3 × 20 mL). The combined organic extracts were dried (MgSO4)
IR (KBr): 3140, 2906, 2866, 1468, 1354, 1235, 1146, 1108 cm .
and filtered, and the solvents were removed under reduced pressure.
1
H NMR (600 MHz, CDCl ): δ = 3.58 (s, 4 H), 3.63 (s, 4 H), 3.67–
3
The residue was purified chromatographically (silica gel, CH Cl –
2
2
3.68 (m, 4 H), 3.69–3.72 (m, 4 H), 3.85 (t, J = 5.4 Hz, 4 H), 4.53 (t,
J = 5.4 Hz, 4 H), 4.72 (s, 4 H), 7.87 (s, 2 H).
petroleum ether, 7:3) to give cage diazide 8 as a pale yellow oil;
yield: 357 mg (60%).
13
C NMR (150 MHz, CDCl ): δ = 50.0, 64.9, 69.2, 69.7, 70.1, 70.5
3
IR (film): 930, 1090, 1140, 1259, 1297, 1389, 1457, 1683, 1725,
7
0.6 123.9, 145.4.
–1
2
097, 2865, 2961 cm .
+
HRMS (ESI): m/z [M + H] calcd for C H N O : 427.2305; found:
427.2307.
1
8
31
6
6
1
H NMR (600 MHz, CDCl ): δ = 1.58 (AB, J = 10.5 Hz, 1 H),
3
AB
1.93 (AB, JAB = 10.5 Hz, 1 H), 2.09–2.11 (m, 4 H), 2.44–2.47 (m, 2
H), 2.56–2.59 (m, 4 H), 2.67–2.69 (m, 2 H), 3.37– 3.45 (m, 4 H).
Macrocycle 10a (m = 1, n = 1)
Diazide 3a (0.32 mmol) and propargyl derivative 5a (0.32 mmol)
gave macrocycle 10a (m = 1, n = 1). Pale yellow oil; yield: 40 mg
13
C NMR (150 MHz, CDCl ): δ = 31.6, 41.6, 43.6, 44.2, 48.0, 48.1,
3
58.8, 94.3.
(
35%).
MS (CI): m/z = 299.1 [M + 1]+.
–
1
IR (KBr): 3129, 2916, 2862, 1465, 126, 1093, 1050 cm .
Anal. Calcd for C H N O: C, 60.37; H, 6.08; N, 28.18. Found: C,
1
5
18
6
1
H NMR (600 MHz, CDCl ): δ = 2.85 (t, J = 6 Hz, 4 H), 3.79 (t,
3
60.11; H, 6.01: N, 27.93.
J = 6 Hz, 4 H), 3.8 (t, J = 4.8 Hz, 4 H), 4.52 (t, J = 4.8 Hz, 4 H), 4.70
(
s, 4 H), 7.49 (s, 2 H).
Preparation of Macrocycles
13
C NMR (150 MHz, CDCl ): δ = 32.1, 50.3, 64.5, 69.4, 71.2,
23.4, 145.6.
3
Macrocycle 9a (m = 1, n = 1); Typical Procedure under Aqueous
Conditions
1
+
To a stirred soln of CuSO (26 mg, 0.14 mmol) and sodium ascor-
HRMS (EI): m/z [M] calcd for C H N O S: 354.1474; found:
354.1469.
4
14 22
6
3
bate (190 mg, 0.96 mmol) in a degassed mixture of H O–MeOH
2
(2:1, 50 mL), a soln of diazide 3a (0.32 mmol) and propargyl deriv-
ative 4a (0.32 mmol) in a degassed mixture of H O–MeOH (2:1, 50
Macrocycle 10b (m = 2, n = 1)
Diazide 3b (0.32 mmol) and propargyl derivative 5a (0.32 mmol)
gave macrocycle 10b (m = 2, n = 1). Pale yellow oil; yield: 44 mg
2
mL) was added dropwise at 60 °C over 6 h under a argon atmo-
sphere, and the resulting mixture was stirred for 24 h at this temper-
ature. The soln was cooled to r.t., and then it was extracted with
(
44%).
CH Cl (2 × 40 mL). The combined organic layers were dried
IR (KBr): 3138, 2919, 2867, 1463, 1359, 1223, 1104 cm–1.
2
2
(
MgSO ) and filtered, and the filtrate was concentrated under re-
4
1
H NMR(600 MHz, CDCl ): δ = 2.79 (t, J = 6.0 Hz, 4 H), 3.58 (s, 4
3
duced pressure. The residue was purified by filtration through a sil-
ica gel pad (EtOAc, then 5% MeOH–CH Cl ) to give macrocycle
H), 3.76 (t, J = 6.0 Hz, 4 H), 3.86 (t, J = 4.8 Hz, 4 H), 4.53 (t, J = 4.8
Hz, 4 H), 4.69 (s, 4 H), 7.82 (s, 2 H).
2
2
9a (m = 1, n = 1) as a pale yellow oil; yield: 30 mg (27%).
13
C NMR (150 MHz, CDCl ): δ = 32.1, 50.3, 64.7, 69.4, 70.3, 70.8,
3
1
23.7, 145.3.
+
HRMS (EI): m/z [M] calcd for C H N O S: 398.1736; found:
1
6
26
6
4
3
98.1726.
Synthesis 2013, 45, 2245–2250
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Cookson’s Birdcage-Derived Thiacrown Ethers
2249
Macrocycle 10c (m = 1, n = 2)
Diazide 3a (0.32 mmol) and propargyl derivative 5b (0.32 mmol)
gave macrocycle 10c (m = 1, n = 2). Pale yellow oil; yield: 75 mg
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
(50%).
–
1
References
IR (KBr): 3134, 2915, 2862, 1448, 1366, 1219, 1113, 1053 cm .
1
H NMR (600 MHz, CDCl ): δ = 2.78–2.80 (m, 4 H), 2.87 (s, 4 H),
.80–3.85 (m, 8 H), 4.52 (t, J = 4.8 Hz, 4 H), 4.71 (s, 4 H), 7.54 (s,
(1) Meadow, J. R.; Reid, E. E. J. Am. Chem. Soc. 1934, 56,
2177.
3
3
2
H).
(2) (a) Baumann, T. F.; Reynolds, J. G.; Fox, G. A. React.
Funct. Polym. 2000, 44, 111. (b) Fedorova, O. A.; Fedorov,
Y. V.; Vedernikov, A. I.; Gromov, S. P.; Yescheulova, O.
V.; Alfimov, M. V.; Woerner, M.; Bossmann, S.; Braun, A.;
Saltiel, J. J. Phys. Chem. A 2002, 106, 6213. (c) Minkin, V.
I.; Dubonosov, A. D.; Bren, V. A.; Tsukanov, A. V.
ARKIVOC 2008, (iv), 90. (d) Lee, T. K.-M.; Zhu, N.; Yam,
V. W.-W. J. Am. Chem. Soc. 2010, 132, 17646. (e) Ingram,
J. D.; Costa, P. J.; Adams, H.; Ward, M. D.; Félix, V.;
Thomas, J. A. Inorg. Chem. 2012, 51, 10483. (f) Grant, G. J.
Dalton Trans. 2012, 41, 8745.
13
C NMR (150 MHz, CDCl ): δ = 50.0, 64.9, 69.2, 69.7, 70.1, 70.6,
3
123.9, 145.4.
+
HRMS (EI): m/z [M] calcd for C H N O S : 414.1508; found:
1
6
26
6
3 2
414.1513.
Macrocycle 10d (m = 2, n = 2)
Diazide 3b (0.32 mmol) and propargyl derivative 5b (0.32 mmol)
gave macrocycle 10d (m = 2, n = 2). Pale yellow oil; yield: 45 mg
(39%).
–1
IR (KBr): 3136, 2919, 2866, 1463, 1357, 1223, 1103 cm .
(
3) Siswanta, D.; Nagatsuka, K.; Yamada, K.; Kumakura, K.;
Hisamoto, H.; Shichi, Y.; Toshima, K.; Suzuki, K. Anal.
Chem. 1996, 68, 4166.
1
H NMR (600 MHz, CDCl ): δ = 2.74 (t, J = 6.0 Hz, 4 H), 2.78 (s,
3
4
H), 3.60 (s, 4 H), 3.78 (t, J = 6.0 Hz, 4 H), 3.86 (t, J = 4.8 Hz, 4
H), 4.55 (t, J = 4.8 Hz, 4 H), 4.71 (s, 4 H), 7.82 (s, 2 H).
(4) (a) Cookson, R. C.; Grundwell, E.; Hudec, J. Chem. Ind.
(London) 1958, 1003. (b) Marchand, A. P.; Allen, R. W.
J. Org. Chem. 1974, 39, 1596.
13
C NMR (150 MHz, CDCl ): δ = 32.7, 33.2, 50.3, 64.5, 69.2, 70.5,
3
70.8, 123.9, 144.8.
(5) (a) Marchand, A. P.; Kumar, K. A.; McKim, A. S.; Mlinarić-
Majerski, K.; Kragol, G. Tetrahedron 1997, 53, 3467.
+
HRMS (EI): m/z [M] calcd for C H N O S : 458.1770; found:
1
8
30
6
4 2
458.1757.
(
9
b) Marchand, A. P.; Chong, H.-S. Tetrahedron 1999, 55,
697. (c) Marchand, A. P.; Cal, D.; Mlinarić-Majerski, K.;
Ejsmont, K.; Watson, W. H. J. Chem. Crystallogr. 2002, 32,
47.
Macrocycle 11a (n = 1)
Cage diazide 8 (0.185 mmol) and propargyl derivative 5a (0.185
mmol) gave macrocycle 11a (n = 1). Note: degassed MeCN was
used in double amount (2 × 100 mL); time of reaction 48 h. Pale yel-
low oil; yield: 62 mg (75%).
4
(
6) For the synthesis and biological activity of selected
pentacycloundecane-derived compounds, see: (a) Oliver, D.
W.; Malan, S. F. Med. Chem. Res. 2008, 17, 137. (b) Wilkes,
D. K.; de Vries, A.; Oliver, D. W.; Malan, S. F. Arch. Pharm.
IR (KBr): 2958, 2863, 1663, 1459, 1370, 1296, 1222, 1080, 1049,
–
1
931, 785 cm .
(Weinheim, Ger.) 2009, 342, 73. (c) Onajole, O. K.; Sosibo,
1
H NMR (600 MHz, CDCl ): δ = 1.59 (AB, J = 10.8 Hz, 1 H),
S.; Govender, P.; Govender, T.; van Helden, P. D.; Maguire,
G. E. M.; Mlinarić-Majerski, K.; Wiid, I.; Kruger, H. G.
Chem. Biol. Drug Des. 2011, 78, 1022. (d) Wang, J.; Ma, C.;
Balannik, V.; Pinto, L. H.; Lamb, R. A.; DeGrado, W. F.
Med. Chem. Lett. 2011, 2, 307. (e) Karpoormath, R.; Sayed,
Y.; Govender, P.; Govender, T.; Kruger, H. G.; Soliman, M.
E. S.; Maguire, G. E. M. Bioorg. Chem. 2012, 40, 19.
7) (a) Wu, G.; Jiang, W.; Lamb, J. D.; Bradshaw, J. S.; Izatt, R.
M. J. Am. Chem. Soc. 1991, 113, 6538. (b) Edema, J. J. H.;
Buter, J.; Schoonbeek, F. S.; Kellogg, R. M.; van Bolhuis,
F.; Spek, A. L. Inorg. Chem. 1994, 33, 2448. (c) Lange, S.
J.; Sibert, J. W.; Barrett, A. G. M.; Hoffman, B. M.
3
AB
1.94 (AB, JAB = 10.8 Hz, 1 H), 2.29–2.37 (m, 6 H), 2.38–2.43 (m, 6
H), 2.52 (t, J = 3.6 Hz, 4 H), 2.85 (t, J = 6.6 Hz, 4 H), 3.82 (t, J = 6.6
Hz, 4 H), 4.69 (s, 4 H), 7.71 (s, 2 H).
13
C NMR (600 MHz, CDCl ): δ = 31.5, 32.4, 41.4, 43.7, 43.9, 46.9,
3
47.8, 58.5, 65.2, 71.6, 94.3, 122.9, 145.1.
+
HRMS (ESI): m/z [M + H] calcd for C H N O S: 497.2335;
found, 497.2339.
2
5
33
6
3
(
Macrocycle 11b (n = 2)
Cage diazide 8 (0.185 mmol) and propargyl derivative 5b (0.185
mmol) gave macrocycle 11b (n = 2). Pale yellow oil; yield: 75 mg
(
80%).
Tetrahedron 2000, 56, 7371. (d) Tsuchiya, T.; Shimizu, T.;
Kamigata, N. J. Am. Chem. Soc. 2001, 123, 11534.
IR (KBr): 2957, 2862, 1654, 1458, 1296, 1221, 1100, 1049, 778
cm .
–1
(8) (a) Latyshev, G. V.; Baranov, M. S.; Kazantsev, A. V.;
Averin, A. D.; Lukashev, N. V.; Beletskaya, I. P. Synthesis
2009, 2605. (b) Binauld, S.; Hawker, C. J.; Fleury, E.;
Drockenmuller, E. Angew. Chem. 2009, 121, 6782; Angew.
Chem. Int. Ed. 2009, 48, 6654.
9) (a) Huisgen, R. Proc. Chem. Soc., London 1961, 357.
(b) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057. (c) Rostovtsev, V. V.; Green, L. G.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem. 2002, 114,
1
H NMR (600 MHz, CDCl ): δ = 1.54 (AB, J = 12.0 Hz, 1 H),
3
AB
1
.87 (AB, JAB = 12.0 Hz, 1 H), 2.30–2.36 (m, 8 H), 2.36–2.40 (m, 8
H), 2.66 (t, J = 6.0 Hz, 4 H), 3.72 (t, J = 6.0 Hz, 4 H), 4.42 (t,
J = 12.0 Hz, 4 H), 4.65 (s, 4 H), 7.65 (s, 2 H).
(
13
C NMR (150 MHz, CDCl ): δ = 31.6, 32.3, 32.9, 41.3, 43.6, 43.8,
6.9, 47.8, 58.7, 64.8, 71.2, 94.2, 123.4, 144.7.
3
4
+
HRMS (FAB): m/z [M + H] calcd for C H N O S : 557.2369;
found: 557.2376.
2
7
37
6
3 2
2708; Angew. Chem. Int. Ed. 2002, 41, 2596.
(
(
10) (a) Bonger, K. M.; van der Berg, R. J. B. H. N.; Heitman, L.
H.; IJzerman, A. P.; Oosterom, J.; Timmers, C. M.;
Overkleeft, H. S.; van der Marel, G. A. Bioorg. Med. Chem.
Acknowledgment
2
007, 15, 4841. (b) Gao, Y.; Chen, L.; Zhang, Z.; Gu, W.; Li,
Authors acknowledge financial support from National Science
Center (Grant No. DEC-2011/01/B/ST5/06613).
Y. Biomacromolecules 2010, 11, 3102.
11) See ref. 77 in: Kolb, H. C.; Finn, M. G.; Sharpless, K. B.
Angew. Chem. 2001, 113, 2056; Angew. Chem. Int. Ed.
2
001, 40, 2004.
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2245–2250

2
250
M. Stefaniak et al.
PAPER
monitoring, permanganate stain). After filtration through
(
12) Yao, Z.-J.; Wu, H.-P.; Wu, Y.-L. J. Med. Chem. 2000, 43,
484.
2
Celite and purification on short column (silica gel, hexanes–
(
13) Since the original protocol (see ref. 5a) used hazardous
CHCl , 1:1) compound 6 was isolated (2.83 g, 74% yield for
2
benzene for azeotropic removal of H O, we were pleased to
2 steps).
2
find that a large excess of freshly dried MgSO was also
(14) Blair, S. M.; Brodbelt, J. S.; Marchand, A. P.; Kumar, K. A.;
Chong, H.-S. Anal. Chem. 2000, 72, 2433.
(15) Gokel, W. G. In Encyclopedia of Supramolecular
Chemistry; Vol. 1; Atwood, J. L.; Steed, J. W., Eds.; CRC
Press: New York, 2004, 326.
4
sufficient. In a typical procedure, the crude diol prepared
from diketone 1 (3.12 g, 17.9 mmol) was dissolved in anhyd
CH Cl (250 mL), anhyd MgSO (22.0 g. 0.18 mol) followed
2
2
4
by TsOH·H O (1.0 g, 5.26 mmol) were added, and the
2
resulting mixture was vigorously stirred for 2 d at r.t. (TLC
Synthesis 2013, 45, 2245–2250
© Georg Thieme Verlag Stuttgart · New York