Copper-catalyzed [1,3]-dipolar cycloaddition for the synthesis of macrocycles containing acyclic, aromatic and steroidal moieties

Article abstract of DOI:10.1055/s-0029-1217400

Copper-catalyzed 1,3-dipolar cycloaddition reactions are used for the synthesis of a series of bis(1,2,3-triazole)-containing macrocycles possessing acyclic, aromatic and steroidal fragments. The influence of the nature of the substituents on the diazides

Full text of DOI:10.1055/s-0029-1217400

PAPER
2605
Copper-Catalyzed [1,3]-Dipolar Cycloaddition for the Synthesis of
Macrocycles Containing Acyclic, Aromatic and Steroidal Moieties
C
opper-Catalyzed
e
[1,3]-Dipol
n
ar Cycloaddi
n
tions adij V. Latyshev, Mikhail S. Baranov, Alexei V. Kazantsev, Alexei D. Averin, Nikolay V. Lukashev,*
Irina P. Beletskaya
Chemistry Department, Moscow State Lomonosov University, Vorobievy Gory, 1, str. 3, 119991 Moscow, Russian Federation
Fax +7(495)4223297; E-mail: nvluk@org.chem.msu.ru
Received 20 March 2009; revised 9 April 2009
possessing triazole groups is of interest because, in addi-
tion to above-mentioned properties, the formation of tri-
azole rings is substantially exothermic9 which can lead to
increased product yields. To date, triazole units have been
Abstract: Copper-catalyzed 1,3-dipolar cycloaddition reactions are
used for the synthesis of a series of bis(1,2,3-triazole)-containing
macrocycles possessing acyclic, aromatic and steroidal fragments.
The influence of the nature of the substituents on the diazides, and
the length of the dialkyne-linking chain, in the substrates, on the introduced into macrocycles via peptides and glycopep-
tides,10 sugars11 and steroids.8 Copper-catalyzed syntheses
product yields is studied. Macrocycles containing steroidal frag-
ments are prepared via reactions of bis(cholane)-24,24¢-diazides
of compounds containing several triazole rings conjugat-
with aliphatic dipropargyl esters, or bis(cholane)-24,24¢-dipropar-
ed to an aromatic ring is limited to only a few exam-
gyl esters with aromatic diazides, or by cyclization–dimerization of
ples.7b,12 No reports of aromatic diazides as easily
bile acid derivatives possessing both azide and acetylene groups in
available precursors to such conjugated systems were
found in the literature.
the same molecule.
Key words: 1,3-dipolar cycloaddition, azides, cholaphanes, cop-
per, macrocycles
Herein we report a new approach to triazole-containing
macrocycles which employs a copper-catalyzed 1,3-dipo-
lar cycloaddition. We used aromatic 1a–e, aliphatic 1f–h,
and cholane-containing 1i diazides in reactions with vari-
ous aliphatic and aromatic dipropargyl esters 2a–h, and
cholane-containing dipropargyl esters 2i,j, for the prepa-
ration of the desired macrocycles. The starting diazido-
benzenes 1a–d were obtained by diazotization of
corresponding diamines in the presence of sodium azide.
Bromination of the diazide 1b with dioxane dibromide
gave the bromo-derivative 1e in high yield. The dipropar-
gyl esters 2 were obtained from the corresponding dicar-
boxylic acids by way of esterification according to
standard procedures.
Macrocycles containing bile acid fragments are of sub-
stantial interest because such compounds can be used for
modeling biological systems and for molecular recogni-
tion.1 The rigid lipophilic skeleton of the steroid molecule,
together with the presence of several endocyclic hydroxy
groups, imparts macrocycles derived from bile acids with
high selectivity towards cations, anions and neutral mole-
cules.2 Chola-crown ethers produced from bile acids
readily form complexes with alkali metal ions.3 Ester,
amide and ether fragments have been used as linkers to
bind two bile acid units. We have reported previously that
palladium-catalyzed amination reactions can be employed
for the synthesis of macrocyclic derivatives of bile acids
in unexpectedly high yields.4 This was explained by the
fact that the final macrocyclization step proceeds within
the coordination sphere of the transition metal, which en-
ables favorable orientation of the two reacting fragments
of the intermediate during macrocycle formation. In addi-
tion, metathesis has been proposed for the synthesis of
steroid-containing macrocycles.5
The 1,3-dipolar cycloaddition reaction in toluene in the
presence of copper iodide as catalyst9b proceeded very
slowly. In contrast, bromotris(triphenylphosphine)cop-
per(I) [Cu(PPh3)3Br],13 which is highly soluble in toluene,
turned out to be an excellent catalyst, however, the mac-
rocycles obtained by this method contained triphe-
nylphosphine oxide as a by-product, which could not be
separated out. The best catalyst was found to be copper
triflate (CuOTf) in a toluene–dimethyl sulfoxide mixture
which gave complete reactions within 5 to 10 hours; the
macrocyclic products were easily isolated by column
chromatography. To decrease the concentration of the re-
agents and to achieve a sufficient reaction rate, a dilute
mixture of diacetylene and diazide in toluene was slowly
added to a dimethyl sulfoxide solution of the catalyst.
Following reports of the catalytic effect of copper(I) in the
Huisgen reaction, interest in the synthesis of complexing
agents possessing a 1,2,3-triazole moiety has increased
significantly.6 This approach has several attractive fea-
tures including a simple synthetic procedure, the stability
of triazoles towards many reagents, and the ability of the
triazole group to act both as an inert linker and a complex-
ant for cations7 and anions.8 The synthesis of macrocycles
The reaction of 1,3-diazidobenzene (1a) with dialkynes
2a–c (possessing a C6, C7 or C8 methylene-linking chain)
gave the target macrocycles 3a–c in 9–17% yields
(Scheme 1). Reaction of 1a with dialkynes 2d–h contain-
ing a C3 or C4 methylene-linking chain, or other groups of
similar size, gave only insoluble polymeric products. The
SYNTHESIS 2009, No. 15, pp 2605–2615
Advanced online publication: 22.06.2009
DOI: 10.1055/s-0029-1217400; Art ID: Z04509SS
x
x.
x
x
.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

2606
G. V. Latyshev et al.
PAPER
N
N
N
O
O
O
N
O
O
R2
N
O
R1
Y
R2
N3
R2
N
O
Y
N
N
O
O
CuOTf•0.5C6H6
N
R1
R1
Y
+
+
N
toluene–DMSO
100 °C
N
O
O
N
N3
N
R1
N
O
Y
R2
O
N
O
N
O
O
N
N
1a–e
1a, R1, R2 = H
1b, R1 = Me, R2 = H
1c, R1 = H, R2 = Me
1d, R1 = H, R2 = Cl
2a–h
3a–l 6–17%
3,4 a–c, R1, R2 = H
4k
4l
9%
10%
2a, Y = (CH2)8
2b, Y = (CH2)7
2c, Y = (CH2)6
2d, Y = (CH2)4
2e, Y = CH2OCH2
d–f, R1 = Me, R2 = H
g,h, R1 = H, R2 = Me
i,j, R1 = H, R2 = Cl
k,l, R1 = Me, R2 = Br
1e, R1 = Me, R2 = Br 2f, Y = CH2NPhCH2
2g, Y = thiophene-2,5-diyl
2h, Y = pyridine-2,6-diyl
a,d,g,i,k, Y = (CH2)8
b,e,h,j,l, Y = (CH2)7
c,f, Y = (CH2)6
Scheme 1 Copper-catalyzed 1,3-dipolar cycloaddition of diazides 1a–e with dialkynes 2a–h
N
N
N
O
O
O
N
O
Y
X
Y
N
O
O
Y
O
O
N3
X
N
N
N
O
O
N
CuOTf•0.5C6H6
N
+
+
X
N
N
toluene–DMSO
100 °C
O
Y
O
N3
X
N
O
O
O
N
O
N
N
N
N
1f–h
2a–h
5a–j, 1–18%
5,6 a–c, X = AcOCH
6f,h, trace
1f, X = AcOCH
1g, X = OC(O)(CH2)2N(Ph)(CH2)2OC(O)
1h, X = CH2OCH2
d–h, X = OC(O)(CH2)2N(Ph)(CH2)2OC(O)
i,j, X = CH2OCH2
a,d, Y = (CH2)8
b,e, Y = (CH2)7
c,g, Y = CH2N(Ph)CH2
f,i, Y = CH2OCH2
h,j, Y = thiophene-2,5-diyl
Scheme 2 Preparation of macrocycles 5a–j and cyclodimers 6f,h
presence of weak electron-donating or electron-withdraw- gen, oxygen or sulfur) in both 1f,h and 2e–g enables the
ing substituents on the azides did not influence signifi- possibility of preparing macrocycles of smaller ring size
cantly the yields of the macrocycles 3. The reaction of (for example, 5c,i,j), in comparison to macrocycles 3.
sterically hindered diazide 1e with dialkynes 2a,b gave al- However, the yields of these macrocycles were found to
most equal amounts of compounds 3k,l and cyclodimeric be lower than those obtained from aromatic diazides.
products 4k,l. The yields of these cyclodimers were sub- Macrocycles 5f,h were isolated as 10:1 mixtures with the
stantially higher than those reported in the literature using corresponding cyclodimers 6f,h . We found that the reac-
similar conditions.9b
tions of diprop-2-yn-1-yl pyridine-2,6-dicarboxylate (2h)
with aliphatic or aromatic diazides did not result in mac-
rocyclization. This is in contrast to expectations as favor-
able coordination of copper by the pyridine nitrogen atom
has been reported in the literature.14
We also carried out the reactions of dialkynes 2a–h with
conformationally more labile aliphatic diazides 1f–h in
which the two azide groups are separated by 3–11 atoms
(Scheme 2). The increase in length of the linking chain
between the two azide groups allows macrocycle forma- These data indicate that the optimum size of the macrocy-
tion with dipropargyl esters 2e–g which possess shorter cle in the case of aromatic diazides and aliphatic diprop-
linkers. Interestingly, the presence of heteroatoms (nitro- argyl esters is 21–23 atoms. The use of non-aromatic
Synthesis 2009, No. 15, 2605–2615 © Thieme Stuttgart · New York

PAPER
Copper-Catalyzed [1,3]-Dipolar Cycloadditions
2607
O
O
O
O
O
O
R
O
O
O
CuOTf⋅0.5C6H6
O
R
R
N
toluene–DMSO
100 °C
1a–d
R
+
N
N
R2
R1
O
O
N
N
O
O
7a–d (R = H)
7e (R = OH)
15–24%
18%
N
O
O
a,e, R1, R2 = H
b, R1 = Me, R2 = H
c, R1 = H, R2 = Me
d, R1 = H, R2 = Cl
2i, R = H
2j, R = OH
Scheme 3 The synthesis of bile acid macrocycles 7a–e
O
O
N
O
O
N
Y
N
N
CuOTf•0.5C6H6
N
2a,b,e
+
N
toluene–DMSO
100 °C
O
O
O
N3
N3
O
a, Y = OC(O)(CH2)8C(O)O
b, Y = OC(O)(CH2)7C(O)O
e, Y = OC(O)CH2OCH2C(O)O
1i
8a,b,e
9–16%
Scheme 4 The preparation of bile acid macrocycles 8a,b,e
diazides, or the presence of heteroatoms in the dipropar- steroid-containing products which could not be isolated as
gyl ester chain, affords macrocycles containing 18–29 individual compounds.
atoms in the ring.
Reaction of bis(steroid)-containing diazide 1i with dipro-
To synthesize macrocyclic compounds derived from bile pargyl esters 2a,b,e afforded the corresponding macrocy-
acids we investigated three approaches: i) reaction of cles 8a,b,e (Scheme 4) in lower yields than those obtained
bis(cholane)-24,24¢-dipropargyl esters with aromatic di- with esters 2i and 2j. The formation of cyclodimeric prod-
azides (Scheme 3), ii) reaction of bis(cholane)-24,24¢-di- ucts was also observed with cholaphanes 8a,b (the ratio of
azides with aliphatic dipropargyl esters (Scheme 4) and, cholaphane/cyclodimer was approximately 10:1 after iso-
iii) cyclization–dimerization of bile acid derivatives pos- lation).
sessing azide and acetylene groups in the same molecule
The synthesis of bis(cholane) macrocycles with ‘head-to-
(Scheme 5). The reaction of steroid-containing bis(prop-
tail’ arranged steroidal fragments was carried out under
argyl) esters 2i and 2j with diazidobenzenes 1a–d gave
similar conditions starting from steroids 9a,b (Scheme 5).
cholaphanes 7a–e in yields of 15–24% (Scheme 3). Only
Compounds 10a,b were isolated in pure state in 20–25%
cholaphanes 7a,e could be easily separated from the cor-
yields without contamination with macrocycles of higher
mass.
responding cyclodimers by column chromatography.
Cholaphanes 7b–d were obtained as mixtures with the cy-
clodimers in approximate ratios of 10:1. The reactions of
diesters 2i,j with aliphatic diazides 1g,h gave rise to com-
Hence the use of bile acid derivatives allows the forma-
tion of macrocycles with substantially larger cavity size.
Moreover, some of the products contain hydroxy groups
directed toward the hydrophobic cavity.
plex mixtures of bis- and oligomeric cyclic and linear
Synthesis 2009, No. 15, 2605–2615 © Thieme Stuttgart · New York

2608
G. V. Latyshev et al.
PAPER
R
O
R
O
X
X
O
O
N
N
N3
CuOTf•0.5C6H6
+
N
toluene–DMSO
100 °C
N
N3
O
N
N
X
O
X
O
R
O
R
9a
9b
X = none, R = OH
X = OC(O)CH2, R = H
10a 20%
10b 25%
Scheme 5 The synthesis of bis(cholane) macrocycles 10a,b
N3
N3
COCl
COCl
N
N
O
O
OH
OH
N
O
O
2i
7b
Et3N
CuOTf
24%
N
N
N
11
Scheme 6 Two approaches to macrocycle 7b
CAUTION: Low-molecular weight azides are potentially explo-
sive in nature and should be handled with great care.
Copper-catalyzed 1,3-dipolar cycloaddition as the final
step during cholaphane synthesis was more efficient than
many other approaches to steroid-containing macrocy-
cles. In some of these cases the yields of the final steps
were about 10% or lower, especially when classic synthet-
ic methods were employed.15 In contrast to the easy syn-
thesis of cholaphane 7b via the copper-catalyzed
cycloaddition, only oligomeric products were detected
from the reaction of bis(triazole)-containing dimer 11
with isophthaloyl dichloride (Scheme 6).
Diazidobenzenes 1a–d; General Procedure
A soln of NaNO2 (25 mmol) in H2O (5 mL) was added to an ice-cold
suspension of aromatic diamine (10 mmol) and NaN3 (10 mmol) in
H2SO4 (50%, 10 mL). A second portion of NaN3 (10 mmol) was
added and the resulting soln was allowed to warm to 25 °C over 1
h. The reaction mixture was extracted with Et2O (3 × 30 mL), and
the organic layer washed with 5% aq. NaHCO3 soln (50 mL) and
H2O (2 × 50 mL), dried (Na2SO4) and evaporated under reduced
pressure. The product was purified by flash chromatography (silica
gel, CH2Cl2 or CH2Cl2–hexanes, 1:1).
In summary, the present investigation has demonstrated
the formation of triazole-containing macrocycles, includ-
ing cholaphanes, via copper-catalyzed 1,3-dipolar cy-
cloadditions. Although the synthesis of steroid-containing
macrocycles using palladium-catalyzed amination is more
efficient in some cases, the method described herein al-
lows the use of both lithocholic and deoxycholic acid de-
rivatives.
1,3-Diazidobenzene (1a)16
Yellow-orange liquid; yield: 430 mg (27%); mp 5–7 °C (slowly de-
composes at r.t.).
1H NMR: d = 7.28 (t, 3J = 8.1 Hz, 1 H, H-5), 6.77 (dd, 3J1 = 8.1 Hz,
4J2 = 2.2 Hz, 2 H, H-4,6), 6.60 (t, 4J = 2.2 Hz, 1 H, H-2).
13C NMR: d = 141.7 (C-1,3), 130.7 (C-5), 115.3 (C-4,6), 109.8 (C-
2).
Melting points were measured with a MEL-TEMP II apparatus and
1,3-Diazido-2-methylbenzene (1b)
Yellow-orange solid; yield: 539 mg (31%); mp 80–82 °C.
1
are uncorrected. The H NMR (400 MHz) and 13C NMR (100.6
MHz) spectra were recorded using a Bruker Avance 400 spectrom-
eter in CDCl3. 1H NMR data are presented for key protons only in
the steroid-containing substrates and macrocycles. MALDI-TOF
spectra were recorded on a Bruker Daltonics UltraFlex instrument
using dithranol as the matrix. Elemental analyses were performed
with an Elementar Vario MICRO cube apparatus. Column chro-
matographic separations were carried out on Macherey-Nagel silica
gel 60 (0.040–0.063 mm).
1H NMR: d = 7.23 (t, 3J = 8.0 Hz, 1 H, H-5), 6.89 (d, 3J = 8.0 Hz, 2
H, H-4,6), 2.05 (s, 3 H, CH3).
13C NMR: d = 140.0 (C-1,3), 127.3 (C-5), 114.5 (C-2), 114.0 (C-
4,6), 11.2 (CH3).
Anal. Calcd for C7H6N6: C, 48.27; H, 3.47; N, 48.25. Found: C,
48.10; H, 3.53; N, 48.15.
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Copper-Catalyzed [1,3]-Dipolar Cycloadditions
2609
3
2,4-Diazido-1-methylbenzene (1c)17
Brown crystals; yield: 1.30 g (75%); mp 22–24 °C.
1H NMR: d = 7.09 (d, 3J = 7.9 Hz, 1 H, H-6), 6.69 (m, 2 H, H-3,5),
1H NMR: d = 7.52 (d, J = 7.7 Hz, 6 H, ArH), 7.27–7.15 (m, 9 H,
ArH), 3.60 (m, 2 H, 24-CH2), 3.40 (m, 1 H, 3-CH), 0.92 (d, 3J = 6.2
Hz, 3 H, 21-CH3), 0.79 (s, 3 H, 19-CH3), 0.59 (s, 3 H, 18-CH3).
2.14 (s, 3 H, CH3).
13C NMR: d = 139.7, 138.9 (C-2,4), 132.1 (C-6), 126.3 (C-5), 115.0
(C-1), 108.6 (C-3), 16.6 (CH3).
A mixture of (3a,5b)-3-(trityloxy)cholan-24-ol (605 mg, 1 mmol),
Et3N (0.28 mL, 2 mmol), DMAP (6.1 mg, 0.05 mmol) and MsCl
(0.093 mL, 1.2 mmol) was stirred at 25 °C in CH2Cl2 (4 mL) for
14 h. The reaction mixture was diluted with CH2Cl2 (10 mL),
washed with H2O (10 mL) and the organic layer dried (Na2SO4),
and concentrated under reduced pressure. The crude mesylate
(410.9 mg, 0.60 mmol) in DMSO (2 mL) was stirred with NaN3
(117.3 mg, 1.8 mmol) at 80 °C for 14 h. The reaction mixture was
diluted with CH2Cl2 (10 mL) and washed with H2O (10 mL). The
organic layer was dried (Na2SO4), the solvent evaporated and the
residue purified by column chromatography (CH2Cl2–hexanes,
1:2).
2,4-Diazido-1-chlorobenzene (1d)
Yellow solid; yield: 290 mg (15%); mp 29–32 °C.
1H NMR: d = 7.32 (d, 3J = 9.9 Hz, 1 H, H-6), 6.75 (m, 2 H, H-3,5).
13C NMR: d = 140.1 (C-1), 138.5 (C-3), 131.6 (C-2), 121.1 (C-4),
116.1 (C-6), 110.3 (C-5).
Anal. Calcd for C6H3N6Cl: C, 37.04; H, 1.55; N, 43.19. Found: C,
37.34; H, 1.57; N, 43.10.
Colorless oil; yield: 311 mg (82%).
1H NMR: d = 7.50 (d, 3J = 7.7 Hz, 6 H, ArH), 7.27–7.17 (m, 9 H,
ArH), 3.40 (m, 1 H, 3-CH), 3.21 (m, 2 H, 24-CH2), 0.90 (d, 3J = 6.4
Hz, 3 H, 21-CH3), 0.75 (s, 3 H, 19-CH3), 0.59 (s, 3 H, 18-CH3).
1,3-Diazido-4-bromo-2-methylbenzene (1e)
A soln of 1,3-diazido-2-methylbenzene (1b) (174 mg, 1 mmol) and
dioxane dibromide (296 mg, 1.2 mmol) in Et2O–AcOH (10:1, 2.2
mL) was stirred at 25 °C for 48 h. The reaction mixture was diluted
with Et2O (20 mL) and then washed with aq Na2SO3 soln (10 mL)
and H2O (10 mL). The organic layer was dried (Na2SO4) and the
crude residue purified by column chromatography.
A mixture of (3a,5b)-24-azido-3-(trityloxy)cholane (247 mg, 0.39
mmol) and concd HCl (0.3 mL) in EtOH (95%, 3 mL) was heated
at reflux for 4 h. After cooling, the product was extracted with
CH2Cl2 (2 × 10 mL). The combined organic layer was washed with
H2O (10 mL), dried (Na2SO4), the solvent evaporated and the resi-
due purified by column chromatography (CH2Cl2–EtOH, 50:1).
Yellowish crystals; yield: 202 mg (80%); mp 51–53 °C.
1H NMR: d = 7.39 (d, 3J = 8.7 Hz, 1 H, H-5), 6.84 (d, 3J = 8.7 Hz, 1
H, H-6), 2.22 (s, 3 H, CH3).
13C NMR: d = 139.1, 138.0 (C-1,3), 131.4 (C-5), 126.0 (C-2), 116.4
(C-6), 113.6 (C-4), 13.0 (CH3).
Colorless oil; yield: 107 mg (70%).
1H NMR: d = 3.59 (m, 1 H, 3-CH), 3.20 (m, 2 H, 24-CH2), 0.90 (m,
6 H, 2 CH3), 0.63 (s, 3 H, 18-CH3).
13C NMR: d = 71.7 (3-CH2), 56.4, 56.0, 51.9, 42.6, 42.0, 40.4, 40.1,
36.3, 35.8, 35.4, 35.3, 34.5, 32.8, 30.4, 28.2, 27.1, 26.4, 25.4, 24.1,
23.3, 20.7, 18.5, 11.9.
2-Acetoxy-1,3-diazidopropane (1f)18
A mixture of 1,3-diazidopropan-2-ol19 (2 g, 15 mmol), Et3N (2 g,
2.7 mL, 20 mmol) and Ac2O (2.0 g, 20 mmol) in CH2Cl2 (10 mL)
was heated at reflux for 2 h. After cooling, the reaction mixture was
washed with H2O (3 × 20 mL), the solvent evaporated and the prod-
uct purified by flash chromatography (CH2Cl2–EtOH, 50:1).
A mixture of (3a,5b)-24-azidocholan-3-ol (1.192 g, 3.08 mmol),
Et3N (1.64 mL, 12.3 mmol), DMAP (18.8 mg, 0.15 mmol) and
isophthaloyl dichloride (0.312 g, 1.54 mmol) in toluene (8 mL) was
stirred at 60 °C for 4 h. The reaction mixture was diluted with
CH2Cl2 (20 mL), the organic layer washed with H2O (20 mL) and
dried (Na2SO4). Following evaporation of the solvent, the residue
was purified by column chromatography (CH2Cl2).
Colorless oil; yield: 2.2 g (85%).
3
3
1H NMR: d = 5.05 (quint, J = 5.2 Hz, 1 H, CH), 3.47 (d, J = 5.2
Hz, 4 H, CH2), 2.12 (s, 3 H, CH3).
13C NMR: d = 169.9 (CO), 70.8 (CH), 50.7 (CH2), 20.6 (CH3).
White solid; yield: 1.083 g (78%); mp 123–126 °C.
1H NMR: d = 8.68 (t, 4J = 1.7 Hz, 1 H, ArH-2), 8.19 (dd, 3J1 = 7.8
Hz, 4J2 = 1.7 Hz, 2 H, ArH-4,6), 7.49 (t, 3J = 7.8 Hz, 1 H, ArH-5),
4.98 (m, 2 H, 3-CH), 3.21 (m, 4 H, 24-CH2), 0.96 (s, 6 H, 19-CH3),
0.92 (d, 3J = 6.5 Hz, 6 H, 21-CH3), 0.65 (s, 6 H, 18-CH3).
13C NMR: d = 165.4 (CO), 133.4 (ArC-5), 131.3 (ArC-1), 130.8
(ArC-2), 128.3 (ArC-4,6), 75.4 (3-CH2), 56.4, 56.1, 51.9, 42.7,
41.9, 40.5, 40.1, 35.8, 35.4, 35.1, 34.6, 32.9, 32.3, 28.3, 27.0, 26.7,
26.3, 25.5, 24.2, 23.3, 20.9, 18.6, 12.0.
Bis[(3a,5b)-24-azidocholan-3-yl] Isophthalate (1i)
A soln of methyl lithocholate (1.148 g, 2.94 mmol), Et3N (1.63 mL,
11.7 mmol), DMAP (0.072 g, 0.59 mmol) and trityl chloride (1.229
g, 4.41 mmol) in CH2Cl2 (8 mL) was heated in a sealed tube at 90
°C for 20 h. The reaction mixture was diluted with CH2Cl2 (20 mL),
washed with H2O (2 × 20 mL), and the organic layer dried (Na2SO4)
and concentrated under reduced pressure. The tritylated product
was purified by column chromatography (hexanes–CH2Cl2, 1:1).
Colorless oil; yield: 1.54 g (83%).
Synthesis of Dipropargylic Esters (2a–e,g,h); General Proce-
dure
3
1H NMR: d = 7.50 (d, J = 7.8 Hz, 6 H, ArH), 7.28–7.18 (m, 9 H,
ArH), 3.65 (s, 3 H, CH3), 3.40 (m, 1 H, 3-CH), 2.34 (m, 1 H, 23-
CH2), 2.21 (m, 1 H, 23-CH2), 0.88 (d, J = 6.2 Hz, 3 H, 21-CH3),
0.74 (s, 3 H, 19-CH3), 0.59 (s, 3 H, 18-CH3).
Acid dichloride (1 mmol), propargyl alcohol (2.5 mmol), Et3N (3
mmol) and DMAP (0.4 mmol) in CH2Cl2 (5 mL) were heated at re-
flux for 3 h. The reaction mixture was diluted with CH2Cl2 (20 mL)
and the organic layer washed with 5% HCl (10 mL), 5% aq
NaHCO3 soln (10 mL) and H2O (10 mL), and then dried (Na2SO4)
and concentrated under reduced pressure. Solid esters 2e, 2g, and 2h
were purified by trituration with Et2O (2 × 1 mL) and then dried. Es-
ters 2a–d were purified by flash chromatography (CH2Cl2).
3
Methyl (3a,5b)-3-(trityloxy)cholan-24-oate (1.60 g, 2.53 mmol)
and LiAlH4 (0.14 g, 3.79 mmol) were heated at reflux for 2 h in THF
(5 mL). The reaction mixture was cooled to 10 °C, followed by di-
lution with H2O (20 mL). The solids were removed by filtration and
the product was extracted with CH2Cl2 (2 × 20 mL). The combined
organic layer was washed with 5% HCl (30 mL), 5% Na2CO3 soln
(30 mL) and H2O (30 mL), dried (Na2SO4) and concentrated under
reduced pressure. No further purification was necessary.
Diprop-2-yn-1-yl 2,2¢-(Phenylimino)diacetate (2f)
2,2¢-(Phenylimino)diacetic acid20 (5.2 g, 25 mmol) and N,N¢-carbo-
nyl diimidazole (CDI) (9.7 g, 60 mmol) in CHCl3 (100 mL) were
heated at reflux for 2 h. Propargyl alcohol (3.4 g, 60 mmol) was add-
Colorless oil; yield: 1.53 g (100%).
Synthesis 2009, No. 15, 2605–2615 © Thieme Stuttgart · New York

2610
G. V. Latyshev et al.
PAPER
ed and reflux was continued for 3 h. The reaction mixture was
washed with H2O (2 × 50 mL), dried (Na2SO4) and concentrated un-
der reduced pressure.
A mixture of the 3b-mesylate (750 mg, 1.5 mmol) and NaN3 (200
mg, 3.5 mmol) in DMSO (20 mL) was stirred at 70 °C for 6 h. The
reaction mixture was diluted with CH2Cl2 (30 mL), washed with
H2O (3 × 20 mL), and the organic layer dried (Na2SO4) and evapo-
rated. The residue was purified by column chromatography
(CH2Cl2–EtOH, 99:1).
White solid; yield: 5.8 g (85%); mp 83–84 °C.
1H NMR: d = 7.21 (t, 3J = 7.5 Hz, 2 H, ArH-3), 6.80 (t, 3J = 7.3 Hz,
1 H, ArH-4), 6.61 (d, 3J = 7.8 Hz, 2 H, ArH-2), 4.75 (d, 4J = 2.4 Hz,
4 H, CCH2), 4.19 (s, 4 H, NCH2), 2.49 (t, 4J = 2.4 Hz, 2 H, CCH).
13C NMR: d = 170.1 (CO), 147.4 (ArC-1), 129.3 (ArC-3,5), 118.8
(ArC-4), 112.7 (ArC-2,6), 77.1 (C), 75.4 (CH), 53.2 (CH2), 52.5
(CH2).
White solid; yield: 520 mg (75%); mp 156–158 °C.
4
1H NMR: d = 5.16 (m, 1 H, 3-CH), 4.66 (d, J = 2.1 Hz, 2 H,
4
OCH2C), 3.96 (m, 1 H, 12-CH), 2.45 (t, J = 2.1 Hz, 1 H, CCH),
2.39 (m, 1 H, 23-CH2), 2.29 (m, 1 H, 23-CH2), 0.96 (m, 6 H, 2 CH3),
0.66 (s, 3 H, 18-CH3).
Anal. Calcd for C16H15NO4: C, 67.36; H, 5.30; N, 4.91. Found: C,
67.54; H, 5.48; N, 5.11.
Synthesis of a-Chloroacetates; General Procedure
A mixture of alcohol (1 mmol), chloroacetic anhydride (1 mmol),
Et3N (1.5 mmol) and DMAP (0.2 mmol) in CH2Cl2 (15 mL) was
stirred at 25 °C for 1 h. The reaction mixture was washed with H2O
(2 × 10 mL), the organic layer dried (Na2SO4), evaporated and pu-
rified by column chromatography (CH2Cl2–EtOH, 100:1).
Bis[(3a,5b)-24-oxo-24-(propargyloxy)cholan-3-yl] Isophthalate
(2i)
Propargyl lithocholate (2.1 g, 5 mmol), Et3N (1.5 g, 2 mL, 15
mmol), DMAP (15 mg, 0.12 mmol) and isophthaloyl dichloride (0.5
g, 2.5 mmol) were heated at reflux in toluene (30 mL) for 4 h. The
reaction mixture was diluted with CH2Cl2 (30 mL), washed with
H2O (2 × 50 mL) and the organic layer dried (Na2SO4) and concen-
trated under reduced pressure. The product was purified by column
chromatography (CH2Cl2).
N,N-Di[(chloroacetoxy)ethyl]aniline
Colorless oil; yield: 6.6 g (75%).
1H NMR: d = 7.23 (t, 3J = 8.2 Hz, 2 H, ArH-3,5), 6.74 (m, 3 H, ArH-
2,4,6), 4.35 (t, 3J = 6.1 Hz, 4 H, CH2), 4.01 (s, 4 H, CH2), 3.66 (t,
3J = 6.1 Hz, 4 H, CH2).
13C NMR: d = 167.2 (CO), 146.8 (ArC-1), 129.5 (ArC-3,5), 117.5
(ArC-4), 112.3 (ArC-2,6), 63.1 (CH2), 49.5 (CH2), 40.6 (CH2Cl).
White foam; yield: 2.1 g (85%); mp 103–106 °C.
1H NMR: d = 8.68 (t, 4J = 1.8 Hz, 1 H, ArH-2), 8.19 (dd, 3J1 = 7.7
Hz, 4J2 = 1.8 Hz, 2 H, ArH-4,6), 7.49 (t, 3J = 7.7 Hz, 1 H, ArH-5),
4
4.98 (m, 2 H, 3-CH), 4.66 (d, J = 2.3 Hz, 4 H, OCH2C), 2.45 (t,
4J = 2.4 Hz, 2 H, CCH), 2.39 (m, 2 H, 23-CH2), 2.28 (m, 2 H, 23-
CH2), 0.95 (s, 6 H, 19-CH3), 0.91 (d, 3J = 6.3 Hz, 6 H, 21-CH3), 0.62
(s, 6 H, 18-CH3).
Propargyl (3a,5b)-3-(Chloroacetoxy)cholan-24-oate
Colorless foam; yield: 402 mg (80%).
4
1H NMR: d = 4.80 (m, 1 H, 3-CH), 4.66 (d, J = 2.4 Hz, 2 H,
OCH2C), 4.02 (s, 2 H, CH2Cl), 2.46 (t, 4J = 2.4 Hz, 1 H, CCH), 2.37
(m, 1 H, 23-CH2), 2.26 (m, 1 H, 23-CH2), 0.90 (s, 3 H, 21-CH3),
0.89 (s, 3 H, 19-CH3), 0.62 (s, 3 H, 18-CH3).
Bis[(3a,5b,12a)-12-hydroxy-24-oxo-24-(propargyloxy)cholan-
3-yl] Isophthalate (2j)
Propargyl deoxycholate (2.5 g, 5.8 mmol), Et3N (1.5 g, 2 mL, 15
mmol), DMAP (15 mg, 0.12 mmol), and isophthaloyl dichloride
(590 mg, 2.9 mmol) were stirred at 25 °C in CH2Cl2 (50 mL) for 20
h. The reaction mixture was diluted with CH2Cl2 (50 mL), washed
with H2O (2 × 50 mL) and the organic layer dried (Na2SO4) and
concentrated under reduced pressure. The product was purified by
column chromatography (CH2Cl2–EtOH, 50:1).
Synthesis of Azides 1g and 9b; General Procedure
A solution of NaN3 (1.5 mmol) and the corresponding chloroacetate
(1 mmol) in DMSO (5 mL) was stirred at 60 °C for 6 h. The reaction
mixture was diluted with CH2Cl2 (20 mL), washed with H2O
(3 × 20 mL), and the organic layer dried (Na2SO4) and evaporated.
The product was purified by column chromatography.
White foam; yield: 1.7 g (60%); mp 115–118 °C.
1H NMR: d = 8.63 (t, 4J = 1.8 Hz, 1 H, ArH-2), 8.19 (dd, 3J1 = 7.6
Hz, 4J2 = 1.8 Hz, 2 H, ArH-4,6), 7.50 (t, 3J = 7.6 Hz, 1 H, ArH-5),
4.98 (m, 2 H, 3-CH), 4.66 (d, 4J = 2.2 Hz, 4 H, OCH2C), 3.99 (m, 2
H, 12-CH), 2.46 (t, 4J = 2.2 Hz, 2 H, CCH), 2.40 (m, 2 H, 23-CH2),
2.29 (m, 2 H, 23-CH2), 0.96 (d, 3J = 6.3 Hz, 6 H, 21-CH3), 0.95 (s,
6 H, 19-CH3), 0.68 (s, 6 H, 18-CH3).
N,N-Di[(azidoacetoxy)ethyl]aniline (1g)
Reaction was carried out at 25 °C for 12 h.
Colorless oil; yield: 4.7 g (70%).
1H NMR: d = 7.23 (t, 3J = 7.3 Hz, 2 H, ArH-3,5), 6.74 (m, 3 H, ArH-
2,4,6), 4.35 (t, 3J = 6.1 Hz, 4 H, CH2), 3.79 (s, 4 H, CH2), 3.65 (t,
3J = 6.1 Hz, 4 H, CH2).
Propargyl (3a,5b,12a)-3-azido-12-hydroxycholan-24-oate (9a)
To a soln of propargyl deoxycholate (0.86 g, 2 mmol), Ph3P (1.60 g,
6 mmol) and MsOH (0.27 mL, 5 mmol) in THF (30 mL) was added
DEAD (1.2 mL of a 40% toluene soln, 6 mmol) under an Ar atm at
40 °C and the reaction stirred at this temperature for 20 h. The reac-
tion mixture was diluted with CH2Cl2 (50 mL), washed with 5%
HCl (20 mL) and H2O (2 × 20 mL), and the organic layer dried
(Na2SO4) and evaporated. The residue was purified by column chro-
matography (CH2Cl2–EtOH, 50:1) to afford the corresponding 3b-
mesylate.
13C NMR: d = 168.3 (CO), 146.9 (ArC-1), 129.5 (ArC-3,5), 117.6
(ArC-4), 112.4 (ArC-2,6), 62.6 (CH2), 50.2 (CH2), 49.4 (CH2).
Propargyl (3a,5b)-3-(Azidoacetoxy)cholan-24-oate (9b)
Colorless solid; yield: 325 mg (80%); mp 137–141 °C.
4
1H NMR: d = 4.83 (m, 1 H, 3-CH), 4.66 (d, J = 2.4 Hz, 2 H,
OCH2C), 3.82 (s, 2 H, CH2N3), 2.45 (t, 4J = 2.4 Hz, 1 H, CCH), 2.38
(m, 1 H, 23-CH2), 2.25 (m, 1 H, 23-CH2), 0.92 (s, 3 H, 19-CH3),
0.90 (d, 3J = 6.3 Hz, 3 H, 21-CH3), 0.63 (s, 3 H, 18-CH3).
Colorless oil; yield: 750 mg (80%).
(2-Methyl-1,3-diazidobenzene)-bis(1H-1,2,3-triazene-1,4-di-
methylene) Bis(3a,5b)-(3-hydroxycholan-24-oate) (11)
A mixture of diazide 1b (110 mg, 0.635 mmol), propargyl lithocho-
late (525 mg, 1.27 mmol), CuSO4·5H2O (15.8 mg, 0.06 mmol) and
sodium ascorbate (25 mg, 0.12 mmol) in THF–H2O (5:1, 6 mL) was
stirred at 40 °C for 24 h. The product was extracted with CH2Cl2
1H NMR: d = 5.02 (m, 1 H, 3-CH), 4.66 (d, J = 2.3 Hz, 2 H,
4
OCH2C), 3.98 (m, 1 H, 12-CH), 2.98 (s, 3 H, Ms), 2.46 (t, 4J = 2.4
Hz, 1 H, CCH), 2.40 (m, 1 H, 23-CH2), 2.27 (m, 1 H, 23-CH2), 0.93
(m, 6 H, 19-CH3, 21-CH3), 0.67 (s, 3 H, 18-CH3).
Synthesis 2009, No. 15, 2605–2615 © Thieme Stuttgart · New York

PAPER
Copper-Catalyzed [1,3]-Dipolar Cycloadditions
2611
(10 mL) and the combined organic layer dried (Na2SO4), evaporat-
ed and purified by column chromatography (CH2Cl2–EtOH, 50:1).
Macrocycle 3d
White solid; yield: 6 mg (13%); mp 208–210 °C.
White solid; yield: 446 mg (70%); mp 167–169 °C.
1H NMR: d = 7.87 [s, 2 H, CH(triazole)], 7.68 (d, 3J = 7.8 Hz, 2 H,
ArH-4,6), 7.58 (t, 3J = 7.8 Hz, 1 H, ArH-5), 5.34 (s, 4 H, CH2), 2.29
(t, 3J = 6.8 Hz, 4 H, CH2), 1.62 (s, 3 H, CH3), 1.46 (m, 4 H, CH2),
1.15–1.05 (m, 8 H, CH2).
13C NMR: d = 173.7 (CO), 143.8 [C(triazole)], 137.5 (ArC-1,3),
130.4 (ArC-2), 128.2 (CH(triazole)], 127.8 (ArC-5), 126.3 (ArC-4),
57.1 (CH2O), 34.2 (CH2), 29.5 (CH2), 29.2 (CH2), 25.6 (CH2), 12.7
(CH3).
1H NMR: d = 7.92 [s, 2 H, CH(triazole)], 7.54 (m, 3 H, ArH), 5.30
(m, 4 H, CH2), 3.60 (m, 2 H, 3-CH), 1.99 (s, 3 H, CH3), 0.89 (m, 12
H, 19,21-CH3), 0.61 (s, 6 H, 18-CH3).
Macrocycles 3a–l, 4k,l, 5a–j, 6f,h, 7a–e, 8a,b,e and 10a,b; Gen-
eral Procedure
To a soln of CuOTf·0.5C6H6 (0.04 mmol) in DMSO (2 mL) was
added, through a dense glass frit, a mixture of the appropriate diaz-
ide (0.2 mmol) and dialkyne (0.2 mmol) in toluene (8 mL) at 100 °C
over 5 h under an Ar atm. The resulting soln was stirred at this tem-
perature for a further 5–10 h after which the reaction mixture was
diluted with CH2Cl2 (15 mL), washed with H2O (3 × 10 mL), and
the organic layer dried (Na2SO4) and evaporated. The product was
purified by column chromatography (CH2Cl2–MeOH). The com-
pounds 5c–h are easily oxidized in air and should be stored under
argon.
MALDI-TOF: m/z [M – 2N2 + H]+ calcd for C23H29N2O4: 397.21;
found: 397.12.
Anal. Calcd for C23H28N6O4: C, 61.05; H, 6.24; N, 18.57. Found: C,
61.37; H, 6.51; N, 18.74.
Macrocycle 3e
White foam; yield: 3 mg (10%).
1H NMR: d = 7.86 [s, 2 H, CH(triazole)], 7.69 (d, 3J = 7.8 Hz, 2 H,
ArH-4,6), 7.57 (t, 3J = 7.7 Hz, 1 H, ArH-5), 5.34 (s, 4 H, CH2), 2.28
(t, 3J = 6.8 Hz, 4 H, CH2), 1.62 (s, 3 H, CH3), 1.45 (m, 4 H, CH2),
1.20–1.05 (m, 6 H, CH2).
Macrocycle 3a
White solid; yield: 8 mg (14%); mp 187–189 °C.
3
4
1H NMR: d = 8.07 (dd, J1 = 8.2 Hz, J2 = 1.7 Hz, 2 H, ArH-4,6),
8.01 [s, 2 H, CH(triazole)], 7.76 (t, 3J = 8.2 Hz, 1 H, ArH-5), 7.45
(t, 4J = 1.7 Hz, 1 H, ArH-2), 5.36 (s, 4 H, CH2), 2.36 (t, 3J = 7.9 Hz,
4 H, CH2), 1.63 (m, 4 H, CH2), 1.35–1.25 (m, 8 H, CH2).
MALDI-TOF: m/z [M – 2N2 + H]+ calcd for C22H27N2O4: 383.20;
found: 383.03.
Macrocycle 3f
White solid; yield: 8 mg (9%); mp 184–186 °C.
1H NMR: d = 7.84 [s, 2 H, CH(triazole)], 7.76 (d, 3J = 7.9 Hz, 2 H,
ArH-4,6), 7.61 (t, 3J = 7.9 Hz, 1 H, ArH-5), 5.36 (s, 4 H, CH2), 2.28
(t, 3J = 7.2 Hz, 4 H, CH2), 1.43 (m, 7 H, CH2,CH3), 1.20 (m, 4 H,
CH2).
13C NMR: d = 173.6 (CO), 145.2 [C(triazole)], 137.8 (ArC-1),
131.9 (ArC-5), 121.7–121.5 [ArC-4,6, CH(triazole)], 112.2 (ArC-
2), 57.9 (CH2O), 33.9 (CH2), 28.8 (CH2), 28.7 (CH2), 24.9 (CH2).
MALDI-TOF: m/z [M + H]+ calcd for C22H27N6O4: 439.21; found:
439.20.
13C NMR: d = 173.7 (CO), 144.2 [C(triazole)], 137.6 (ArC-1,3),
130.5 (ArC-2), 127.9 (ArC-5), 127.6 [CH(triazole)], 126.9 (ArC-
4,6), 57.4 (CH2O), 34.2 (CH2), 29.8 (CH2), 25.9 (CH2), 12.5 (CH3).
Anal. Calcd for C22H26N6O4: C, 60.26; H, 5.98; N, 19.17. Found: C,
60.05; H, 6.01; N, 18.40.
MALDI-TOF: m/z [M – 2N2 + H]+ calcd for C21H25N2O4: 369.18;
found: 369.01.
Macrocycle 3b
White solid; yield: 12 mg (9%); mp 210–212 °C.
3
4
1H NMR: d = 8.11 (dd, J1 = 8.2 Hz, J2 = 1.9 Hz, 2 H, ArH-4,6),
8.05 [s, 2 H, CH(triazole)], 7.75 (t, 3J = 8.2 Hz, 1 H, ArH-5), 7.34
(t, 4J = 1.8 Hz, 1 H, ArH-2), 5.36 (s, 4 H, CH2), 2.40 (t, 3J = 6.3 Hz,
4 H, CH2), 1.63 (m, 4 H, CH2), 1.35–1.25 (m, 6 H, CH2).
Anal. Calcd for C21H24N6O4: C, 59.42; H, 5.70; N, 19.80. Found: C,
59.31; H, 5.95; N, 19.54.
Macrocycle 3g
White solid; yield: 6 mg (13%); mp 151–153 °C.
13C NMR: d = 173.9 (CO), 145.3 [C(triazole)], 137.6 (ArC-1,3),
131.9 (ArC-5), 121.9 [CH(triazole)], 121.7 (ArC-4,6), 111.8 (ArC-
2), 57.8 (CH2O), 33.6 (CH2), 29.8 (CH2), 29.2 (CH2), 24.8 (CH2).
MALDI-TOF: m/z [M + H]+ calcd for C21H25N6O4: 425.20; found:
425.19.
1H NMR: d = 8.08 (dd, 3J1 = 8.3 Hz, 4J2 = 2.2 Hz, 1 H, ArH-6), 7.91
[s, 1 H, CH(triazole)], 7.85 [s, 1 H, CH(triazole)], 7.59 (d, 3J = 8.3
4
Hz, 1 H, ArH-5), 7.24 (d, J = 2.2 Hz, 1 H, ArH-2), 5.34 (m, 4 H,
CH2), 2.34 (m, 7 H, CH2, CH3), 1.55 (m, 4 H, CH2), 1.25–1.15 (m,
8 H, CH2).
13C NMR: d = 133.4 (ArC-5), 125.4 [CH(triazole)], 121.1 (ArC-6),
117.5 (ArC-2), 57.9 (CH2O), 57.2 (CH2O), 33.9 (2 CH2), 28.7
(CH2), 28.7 (CH2), 28.5 (CH2), 28.5 (CH2), 24.9 (CH2), 24.9 (CH2),
17.7 (CH3).
Anal. Calcd for C21H24N6O4: C, 59.42; H, 5.70; N, 19.80. Found: C,
59.41; H, 5.92; N, 19.76.
Macrocycle 3c
White solid; yield: 11 mg (17%); mp 172–174 °C.
MALDI-TOF: m/z [M – 2N2 + H]+ calcd for C23H29N2O4: 397.21;
found: 397.22, 4.
3
4
1H NMR: d = 8.11 (dd, J1 = 8.2 Hz, J2 = 2.0 Hz, 2 H, ArH-4,6),
7.93 [s, 2 H, CH(triazole)], 7.76 (t, 3J = 8.2 Hz, 1 H, ArH-5), 7.21
(t, 4J = 2.0 Hz, 1 H, ArH-2), 5.39 (s, 4 H, CH2), 2.41 (t, 3J = 7.1 Hz,
4 H, CH2), 1.69 (m, 4 H, CH2), 1.39 (m, 4 H, CH2).
Anal. Calcd for C23H28N6O4: C, 61.05; H, 6.24; N, 18.57. Found: C,
61.21; H, 6.35; N, 18.66.
13C NMR: d = 173.4 (CO), 145.9 [C(triazole)], 137.6 (ArC-1,3),
132.1 (ArC-5), 121.5 [CH(triazole)], 120.9 (ArC-4), 111.9 (ArC-2),
58.0 (CH2O), 34.3 (CH2), 29.4 (CH2), 25.5 (CH2).
MALDI-TOF: m/z [M – N2 + Na]+ calcd for C20H22N4NaO4: 405.15;
found: 405.16.
Macrocycle 3h
White solid; yield: 7 mg (15%); mp 197–199 °C.
1H NMR: d = 8.07 (dd, 3J1 = 8.2 Hz, 4J2 = 2.3 Hz, 1 H, ArH-6), 7.92
[s, 1 H, CH(triazole)], 7.86 [s, 1 H, CH(triazole)], 7.59 (d, 3J = 8.2
4
Hz, 1 H, ArH-5), 7.10 (d, J = 1.9 Hz, 1 H, ArH-2), 5.32 (m, 4 H,
Anal. Calcd for C20H22N6O4: C, 58.53; H, 5.40; N, 20.48. Found: C,
58.42; H, 5.39; N, 20.18.
CH2), 2.36 (m, 7 H, CH2, CH3), 1.59 (m, 4 H, CH2), 1.30–1.15 (m,
6 H, CH2).
Synthesis 2009, No. 15, 2605–2615 © Thieme Stuttgart · New York

2612
G. V. Latyshev et al.
PAPER
13C NMR: d = 173.8 (CO), 133.5 (ArC-5), 125.7 [CH(triazole)],
122.7 [CH(triazole)], 121.9 (ArC-6), 117.5 (ArC-2), 57.8 (CH2O),
57.3 (CH2O), 33.8 (CH2), 33.7 (CH2), 29.9 (CH2), 29.3 (CH2), 29.1
(CH2), 24.9 (CH2), 24.9 (CH2), 17.8 (CH3).
(CH2), 29.9 (2 CH2), 28.8 (CH2), 28.7 (CH2), 24.8 (CH2), 24.7
(CH2), 13.9 (CH3).
MALDI-TOF: m/z [M + H]+ calcd for C46H55Br2N12O8: 1061.26;
found: 1061.28.
MALDI-TOF: m/z [M – 2N2 + H]+ calcd for C22H27N2O4: 383.20;
found: 383.18.
Macrocycle 3l
White foam; yield: 12 mg (12%).
Macrocycle 3i
White solid; yield: 5 mg (6%); mp 177–179 °C.
1H NMR: d = 7.89 [s, 1 H, CH(triazole)], 7.88 [s, 1 H, CH(triaz-
ole)], 7.81 (d, 3J = 8.6 Hz, 1 H, ArH-6), 7.59 (d, 3J = 8.6 Hz, 1 H,
ArH-5), 5.58 (d, 2J = 12.3 Hz, 1 H, CH2), 5.45 (d, 2J = 12.3 Hz, 1 H,
CH2), 5.13 (d, 2J = 12.3 Hz, 1 H, CH2), 5.04 (d, 2J = 12.3 Hz, 1 H,
CH2), 2.35 (m, 4 H, CH2), 1.62 (m, 4 H, CH2), 1.43 (s, 3 H, CH3),
1.20–1.00 (m, 6 H, CH2).
13C NMR: d = 131.7 (ArC-6), 127.5 [CH(triazole)], 127.4 [CH(tri-
azole)], 123.3 (ArC-5), 57.2 (CH2O), 56.9 (CH2O), 33.7 (CH2), 33.5
(CH2), 30.8 (CH2), 29.6 (CH2), 29.6 (CH2), 25.0 (CH2), 24.9 (CH2),
13.3 (CH3).
1H NMR: d = 8.21 (dd, 3J1 = 8.8 Hz, 4J2 = 2.5 Hz, 1 H, ArH-5), 8.01
[s, 1 H, CH(triazole)], 7.93 [s, 1 H, CH(triazole)], 7.79 (d, 3J = 7.8
4
Hz, 1 H, ArH-6), 7.44 (d, J = 2.5 Hz, 1 H, ArH-2), 5.35 (m, 4 H,
CH2), 2.32 (m, 4 H, CH2), 1.55 (m, 4 H, CH2), 1.30–1.05 (m, 8 H,
CH2).
13C NMR: d = 173.7 (CO), 173.4 (CO), 145.8 [C(triazole)], 143.6
[C(triazole)], 136.0, 135.5 (ArC-1,4), 132.6 (ArC-6), 129.5 (ArC-
3), 126.2 [CH(triazole)], 123.2 (ArC-5), 120.7 [CH(triazole)], 119.1
(ArC-2), 57.8 (CH2O), 57.8 (CH2O), 34.2 (CH2), 34.1 (CH2), 29.1
(CH2), 29.1 (CH2), 28.9 (CH2), 28.6 (CH2), 25.3 (CH2), 24.2 (CH2).
MALDI-TOF: m/z [M – 2N2]+ calcd for C22H25BrN2O4: 460.10;
found: 460.02.
MALDI-TOF: m/z [M + H]+ calcd for C22H26ClN6O4: 473.17;
found: 473.18.
Macrocycle 4l
White foam; yield: 10 mg (10%).
1H NMR: d = 7.88 [s, 2 H, CH(triazole)], 7.84 [s, 2 H, CH(triaz-
ole)], 7.77 (d, 3J = 8.6 Hz, 2 H, ArH-6), 7.45 (d, 3J = 8.6 Hz, 2 H,
ArH-5), 5.31 (s, 4 H, CH2), 5.28 (s, 4 H, CH2), 2.32 (m, 8 H, CH2),
1.85 (s, 6 H, CH3), 1.57 (m, 8 H, CH2), 1.30–1.15 (m, 12 H, CH2).
Anal. Calcd for C22H25ClN6O4: C, 55.87; H, 5.33; N, 17.77. Found:
C, 55.71; H, 5.51; N, 17.92.
Macrocycle 3j
White solid; yield: 4 mg (8%); mp 210–215 °C (dec.).
1H NMR: d = 8.20 (dd, 3J1 = 8.6 Hz, 4J2 = 2.0 Hz, 1 H, ArH-5), 7.95
13C NMR: d = 132.2 (ArC-6), 127.2 [2 CH(triazole)], 124.1 (ArC-
5), 57.0 (CH2O), 56.8 (CH2O), 34.1 (CH2), 33.9 (CH2), 33.8 (CH2),
29.5 (CH2), 29.5 (CH2), 25.1 (CH2), 24.9 (CH2), 13.3 (CH3).
3
[s, 2 H, CH(triazole)], 7.80 (d, J = 8.6 Hz, 1 H, ArH-6), 7.26 (d,
4J = 1.9 Hz, 1 H, ArH-2), 5.32 (s, 4 H, CH2), 2.35 (q, 3J = 6.1 Hz, 4
H, CH2), 1.60 (m, 4 H, CH2), 1.25–1.00 (m, 6 H, CH2).
MALDI-TOF: m/z [M + H]+ calcd for C44H51Br2N12O8: 1033.23;
found: 1033.71.
13C NMR: d = 132.6 (ArC-6), 126.5 [CH(triazole)], 123.5 (ArC-5),
121.9 [CH(triazole)], 119.4 (ArC-2), 57.8 (CH2O), 57.1 (CH2O),
33.9 (CH2), 33.6 (CH2), 30.2 (CH2), 29.5 (CH2), 29.2 (CH2), 25.1
(CH2), 24.8 (CH2).
Macrocycle 5a
Colorless foam; yield: 1 mg (1%).
MALDI-TOF: m/z [M + K – N2]+ calcd for C21H23ClKN4O4:
469.10; found: 469.11.
1H NMR: d = 7.22 [s, 2 H, CH(triazole)], 5.71 (m, 1 H, CH), 5.29
(s, 4 H, CH2), 4.76–4.49 (m, 4 H, CH2), 2.35 (m, 4 H, CH2), 2.17 (s,
3 H, CH3), 1.65 (m, 4 H, CH2), 1.30–1.10 (m, 8 H, CH2).
Macrocycle 3k
White solid; yield: 12 mg (13%); mp 224–227 °C.
Macrocycle 5b
Colorless foam; yield: 2 mg (2%).
1H NMR: d = 7.20 [s, 2 H, CH(triazole)], 5.70 (m, 1 H, CH), 5.34
(s, 4 H, CH2), 4.76–4.48 (m, 4 H, CH2), 2.35 (m, 4 H, CH2), 2.16 (s,
3 H, CH3), 1.67 (m, 4 H, CH2), 1.35–1.15 (m, 6 H, CH2).
1H NMR: d = 7.84 [s, 2 H, CH(triazole)], 7.81 (d, 3J = 8.6 Hz, 1 H,
ArH-6), 7.58 (d, 3J = 8.6 Hz, 1 H, ArH-5), 5.55 (d, 2J = 12.4 Hz, 1
H, CH2), 5.33 (d, 3J = 4.7 Hz, 2 H, CH2), 5.14 (d, 2J = 12.4 Hz, 1 H,
CH2), 2.27 (m, 4 H, CH2), 1.51 (s, 3 H, CH3), 1.43 (m, 4 H, CH2),
1.15–1.00 (m, 8 H, CH2).
Macrocycle 5c
White solid; yield: 17 mg (18%); mp 192–198 °C.
1H NMR: d = 7.34 [s, 2 H, CH(triazole)], 7.20 (t, 3J = 7.3 Hz, 2 H,
ArH-3), 6.81 (t, 3J = 7.3 Hz, 1 H, ArH-4), 6.67 (d, 3J = 7.3 Hz, 2 H,
ArH-2), 6.48 (m, 1 H, CH), 5.23 (m, 4 H, CH2), 4.39 (m, 4 H, CH2),
4.22 (m, 4 H, CH2), 2.20 (s, 3 H, CH3).
13C NMR: d = 129.4 (ArC-3), 124.5 [CH(triazole)], 118.6 (ArC-4),
112.9 (ArC-2), 69.0 (CH), 58.5 (CH2), 54.2 (CH2), 49.6 (CH2), 20.9
(CH3).
13C NMR: d = 173.7 (CO), 143.9 [C(triazole)], 143.7 [C(triazole)],
136.8, 136.4 (ArC-1,3), 134.6 (ArC-6), 131.6, 129.3 (ArC-2,4),
126.6 [CH(triazole)], 126.2 [CH(triazole)], 123.7 (ArC-5), 59.8
(CH2O), 57.1 (CH2O), 34.3 (CH2), 34.2 (CH2), 29.4 (2 CH2), 29.2
(CH2), 29.1 (CH2), 25.7 (CH2), 25.6 (CH2), 13.2 (CH3).
MALDI-TOF: m/z [M – 2N2 + H]+ calcd for C23H28BrN2O4: 475.12;
found: 475.12.
Anal. Calcd for C23H27BrN6O4: C, 51.98; H, 5.12; N, 15.81. Found:
C, 51.76; H, 5.17; N, 15.49.
MALDI-TOF: m/z [M + H]+ calcd for C21H24N7O6: 470.18; found:
Macrocycle 4k
Colorless foam; yield: 9 mg (9%).
1H NMR: d = 7.86 [s, 2 H, CH(triazole)], 7.83 [s, 2 H, CH(triaz-
ole)], 7.78 (d, 3J = 8.6 Hz, 2 H, ArH-6), 7.45 (d, 3J = 8.6 Hz, 2 H,
ArH-5), 5.32 (s, 4 H, CH2), 5.29 (s, 4 H, CH2), 2.32 (m, 8 H, CH2),
1.84 (s, 6 H, CH3), 1.58 (m, 8 H, CH2), 1.25–1.10 (m, 16 H, CH2).
470.12.
Anal. Calcd for C21H23N7O6: C, 53.73; H, 4.94; N, 20.89. Found: C,
54.03; H, 4.87; N, 20.65.
Macrocycle 5d
White solid; yield: 14 mg (11%); mp 141–143 °C.
13C NMR: d = 173.6 (CO), 143.6 [C(triazole)], 143.4 [C(triazole)],
136.6 (ArC-6), 131.5, 129.2 (ArC-2,4), 125.9 [CH(triazole)], 125.5
[CH(triazole)], 123.8 (ArC-5), 57.2 (2 CH2O), 34.0 (CH2), 33.9
1H NMR: d = 7.66 [s, 2 H, CH(triazole)], 7.24 (t, 3J = 8.7 Hz, 2 H,
ArH-3), 6.76 (t, 3J = 7.3 Hz, 1 H, ArH-4), 6.69 (d, 3J = 8.2 Hz, 2 H,
ArH-2), 5.22 (s, 4 H, CH2), 5.12 (s, 4 H, CH2), 4.33 (t, 3J = 5.8 Hz,
Synthesis 2009, No. 15, 2605–2615 © Thieme Stuttgart · New York

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Copper-Catalyzed [1,3]-Dipolar Cycloadditions
2613
4 H, CH2), 3.52 (t, 3J = 5.8 Hz, 4 H, CH2), 2.31 (t, 3J = 7.2 Hz, 4 H,
CH2), 1.58 (m, 4 H, CH2), 1.30–1.20 (m, 8 H, CH2).
13C NMR: d = 173.7 (CO), 166.2 (CO), 146.9 (ArC-1), 143.6 [C(tri-
azole)], 129.7 (ArC-3), 125.1 [CH(triazole)], 117.8 (ArC-4), 112.5
(ArC-2), 63.4 (CH2), 57.4 (CH2O), 50.8 [CH2(triazole)], 49.5
(CH2), 33.9 (CH2), 28.3 (2 CH2), 24.6 (CH2).
1H NMR: d (5h) = 8.11 [s, 2 H, CH(thienyl)], 7.91 [s, 2 H, CH(tri-
azole)], 7.17 (t, J = 8.3 Hz, 2 H, ArH-3), 6.77 (d, 3J = 8.2 Hz, 2 H,
ArH-2), 6.66 (t, 3J = 7.2 Hz, 1 H, ArH-4), 5.39 (s, 4 H, CH2), 5.33
(s, 4 H, CH2), 4.30 (t, 3J = 6.8 Hz, 4 H, CH2), 3.54 (t, 3J = 6.8 Hz, 4
H, CH2).
MALDI-TOF: m/z [M + H]+ calcd for C26H26N7O8S (5h): 596.16;
found: 596.16.
MALDI-TOF: m/z [M + H]+ calcd for C30H40N7O8: 626.29; found:
626.33.
Macrocycle 5i
Glassy solid; yield: 3 mg (5%).
1H NMR: d = 7.59 [s, 2 H, CH(triazole)], 5.32 (s, 4 H, CH2), 4.52 (t,
3J = 4.5 Hz, 4 H, CH2), 4.23 (s, 4 H, CH2), 3.89 (t, 3J = 4.5 Hz, 4 H,
CH2).
MALDI-TOF: m/z [M + H]+ calcd for C14H18N6O6: 366.11; found:
366.21.
Anal. Calcd for C30H39N7O8: C, 57.59; H, 6.28; N, 15.67. Found: C,
57.75; H, 6.31; N, 15.40.
Macrocycle 5e
Glassy solid; yield: 12 mg (9%); mp 146–149 °C.
1H NMR: d = 7.70 [s, 2 H, CH(triazole)], 7.24 (t, 3J = 7.5 Hz, 2 H,
ArH-3), 6.76 (t, 3J = 7.3 Hz, 1 H, ArH-4), 6.68 (d, 3J = 7.7 Hz, 2 H,
ArH-2), 5.22 (s, 4 H, CH2), 5.15 (s, 4 H, CH2), 4.32 (t, 3J = 5.8 Hz,
4 H, CH2), 3.48 (t, 3J = 5.8 Hz, 4 H, CH2), 2.31 (t, 3J = 7.1 Hz, 4 H,
CH2), 1.56 (m, 4H), 1.30–1.20 (m, 6H).
13C NMR: d = 173.6 (CO), 166.2 (CO), 146.9 (ArC-1), 143.6 [C(tri-
azole)], 129.7 (ArC-3), 125.2 [CH(triazole)], 117.8 (ArC-4), 112.4
(ArC-2), 63.4 (CH2), 57.3 (CH2O), 50.8 [CH2(triazole)], 49.4
(CH2), 33.9 (CH2), 28.0 (CH2), 28.0 (CH2), 24.4 (CH2).
Macrocycle 5j
White solid; yield: 5 mg (5%).
1H NMR: d = 7.81 [s, 2 H, CH(thienyl)], 7.77 [s, 2 H, CH(triazole)],
5.47 (s, 4 H, CH2), 4.63 (t, 3J = 4.5 Hz, 4 H, CH2), 4.01 (t, 3J = 4.5
Hz, 4 H, CH2).
13C NMR: d = 159.6 (CO), 144.0 [C(triazole)], 137.8 (ArC-2),
133.1 (ArC-3), 122.6 [CH(triazole)], 70.4 (CH2O), 60.2 (CH2), 50.8
(CH2).
MALDI-TOF: m/z [M + H]+ calcd for C29H38N7O8: 612.28; found:
612.30.
MALDI-TOF: m/z [M + Na]+ calcd for C16H16N6NaO5S: 427.06;
found: 427.18.
Anal. Calcd for C29H37N7O8: C, 56.95; H, 6.10; N, 16.03. Found: C,
56.84; H, 6.14; N, 16.10.
Macrocycle 7a
Colorless solid; yield: 19 mg (21%); mp 238–240 °C.
Macrocycles 5f and 6f
Glassy solid; yield: 18 mg (7% of a 10:1 macrocycle–cyclodimer
mixture).
1H NMR: d (5f) = 7.62 [s, 2 H, CH(triazole)], 7.26 (t, J = 7.3 Hz, 2
1H NMR: d = 8.53 (s, 1 H, Ar¢H-2), 8.18 [m, 5 H, Ar¢H-4, CH(tria-
zole), ArH-2], 7.85 (d, 3J = 8.2 Hz, 2 H, ArH-4), 7.70 (t, 3J = 8.2 Hz,
1 H, ArH-5), 7.48 (t, 3J = 7.8 Hz, 1 H, Ar¢H-5), 5.30 (m, 4 H, CH2),
4.90 (m, 2 H, 3-CH), 0.93 (s, 6 H, 19-CH3), 0.89 (d, 3J = 5.4 Hz, 6
H, 21-CH3), 0.57 (s, 6 H, 18-CH3).
13C NMR: d = 174.3 (CO), 165.6 (CO), 144.2 [C(triazole)], 137.9
(ArC-5), 133.6 (Ar¢C-4), 131.4 (Ar¢C-5), 128.4 (Ar¢C-2), 122.0
[CH(triazole)], 120.1 (ArC-4), 111.9 (ArC-2), 75.7 (3-CH), 57.2,
56.6, 55.3, 42.6, 41.8, 40.5, 40.1, 35.7, 34.9, 34.8, 34.5, 32.1, 30.8,
30.4, 28.1, 26.9, 26.5, 26.2, 24.1, 23.2, 20.8, 18.3, 11.9.
H, ArH-3), 6.75 (m, 3 H, ArH-2,4), 5.28 (s, 4 H, CH2), 5.07 (s, 4 H,
3
CH2), 4.35 (t, J = 5.8 Hz, 4 H, CH2), 4.22 (s, 4 H, CH2), 3.52 (t,
3J = 5.8 Hz, 4 H, CH2).
13C NMR: d (5f) = 169.4 (CO), 166.3 (CO), 147.2 (ArC-1), 142.8
[C(triazole)], 129.7 (ArC-3), 125.5 [CH(triazole)], 117.9 (ArC-4),
112.6 (ArC-2), 68.2 (CH2), 63.2 (CH2), 58.1 (CH2), 50.7 (CH2),
49.4 (CH2).
MALDI-TOF: m/z [M + H]+ calcd for C24H28N7O9 (5f): 558.20;
found: 558.18.
MALDI-TOF: m/z [M – 2N2 + H]+ calcd for C68H91N2O8: 1063.68;
found: 1063.61.
Anal. Calcd for C24H27N7O9: C, 51.70; H, 4.88; N, 17.39. Found: C,
51.46; H, 4.97; N, 17.38.
Macrocycle 7b
Glassy solid; yield: 20 mg (24% of a 10:1 macrocycle–cyclodimer
mixture).
Macrocycle 5g
Glassy solid; yield: 17 mg (10%).
1H NMR: d = 8.55 (d, 4J = 1.8 Hz, 1 H, Ar¢H-2), 8.17 (dd, 3J1 = 7.7
1H NMR: d = 7.47 [s, 2 H, CH(triazole)], 7.26 (t, 3J = 8.0 Hz, 2 H,
Hz, 4J2 = 1.8 Hz, 2 H, Ar¢H-4), 7.85 [s, 2 H, CH(triazole)], 7.52 (m,
3
3
Ar¢H-3), 7.20 (t, J = 7.3 Hz, 2 H, ArH-3), 6.77 (m, 2 H, ArH-4,
3 H, ArH-4,5), 7.49 (t, J = 7.7 Hz, 1 H, Ar¢H-5), 5.32 (m, 4 H,
Ar¢H-4), 6.70 (d, 3J = 7.9 Hz, 2 H, ArH-2), 6.66 (d, 3J = 7.9 Hz, 2
H, Ar¢H-2), 5.27 (s, 4 H, CH2), 5.04 (s, 4 H, CH2), 4.35 (t, 3J = 5.9
Hz, 4 H, CH2), 4.14 (s, 4 H, CH2), 3.52 (t, 3J = 5.9 Hz, 4 H, CH2).
CH2), 4.92 (m, 2 H, 3-CH), 2.04 (s, 3 H, CH3), 0.94 (s, 6 H, 19-
CH3), 0.88 (d, 3J = 5.9 Hz, 6 H, 21-CH3), 0.61 (s, 6 H, 18-CH3).
MALDI-TOF: m/z [M – 2N2 + H]+ calcd for C69H93N2O8 (macrocy-
13C NMR: d = 170.3 (CO), 166.3 (CO), 147.6, 147.1 (ArC-1, Ar¢C-
1), 143.1 [C(triazole)], 129.7, 129.3 (ArC-3, Ar¢C-3), 125.3
[CH(triazole)], 118.6, 117.9 (ArC-4, Ar¢C-4), 112.9, 112.5 (ArC-2,
Ar¢C-2), 63.2 (CH2), 58.2 (CH2O), 53.6 (CH2), 50.7 [CH2(triazole)],
49.4 (CH2).
cle): 1077.67; found: 1077.59; m/z [M – 2N2 + H]+ calcd for
C158H185N8O16 (cyclodimer): 2211.37; found: 2211.83.
Macrocycle 7c
Glassy solid; yield: 17 mg (16% of a 10:1 macrocycle–cyclodimer
mixture).
MALDI-TOF: m/z [M + H]+ calcd for C30H33N8O8: 633.24; found:
1H NMR: d = 8.51 (d, 4J = 1.6 Hz, 1 H, Ar¢H-2), 8.18 (dd, 3J1 = 7.8
Hz, 4J2 = 1.6 Hz, 2 H, Ar¢H-4), 8.07 [s, 1 H, CH(triazole)], 7.88 [s,
1 H, CH(triazole)], 7.86 (dd, 3J1 = 8.3 Hz, 4J2 = 2.1 Hz, 1 H, ArH-
6), 7.74 (d, 4J = 2.1 Hz, 1 H, ArH-2), 7.55 (d, 3J = 8.3 Hz, 1 H, ArH-
5), 7.50 (t, 3J = 7.8 Hz, 1 H, Ar¢H-5), 5.38–5.23 (m, 4 H, CH2), 4.91
633.22.
Macrocycles 5h and 6h
Colorless solid; yield: 8 mg (2% of a 10:1 macrocycle–cyclodimer
mixture).
Synthesis 2009, No. 15, 2605–2615 © Thieme Stuttgart · New York

2614
G. V. Latyshev et al.
PAPER
(m, 2 H, 3-CH), 2.31 (s, 3 H, CH3), 0.94 (s, 6 H, 19-CH3), 0.89 (d+d,
6 H, 21-CH3), 0.61 (s, 3 H, 18-CH3), 0.57 (s, 3 H, 18-CH3).
Macrocycle 8e
White foam; yield: 13 mg (16%).
MALDI-TOF: m/z [M – 2N2 + H]+ calcd for C69H93N2O8 (macrocy-
cle): 1077.67; found: 1077.88; m/z [M – 2N2 + H]+ calcd for
C158H185N8O16 (cyclodimer): 2211.37; found: 2211.67.
1H NMR: d = 8.55 (d, 4J = 1.5 Hz, 1 H, ArH-2), 8.21 (dd, 3J1 = 7.8
Hz, 4J2 = 1.5 Hz, 2 H, ArH-4), 7.63 [s, 2 H, CH(triazole)], 7.51 (t,
3J = 7.8 Hz, 1 H, ArH-5), 5.28 (s, 4 H, CH2), 4.93 (m, 2 H, 3-CH),
4.31 (m, 4 H, CH2), 4.22 (s, 4 H, CH2), 0.96 (s, 6 H, 19-CH3), 0.91
(d, 3J = 6.6 Hz, 6 H, 21-CH3), 0.64 (s, 6 H, 18-CH3).
13C NMR: d = 169.5 (CO), 165.6 (CO), 142.0 [C(triazole)], 131.7
[CH(triazole)], 128.9 (ArC-2), 125.2 (ArC-4), 123.8 (ArC-5), 75.9
(3-CH), 68.1 (CH2), 58.0 (CH2), 56.5, 55.5, 50.8 (CH2), 42.6, 41.8,
40.5, 40.1, 35.7, 35.0, 34.9, 34.6, 32.4, 32.1, 28.1, 26.9, 26.6, 26.5,
26.3, 24.1, 23.3, 20.8, 18.6 (CH3), 12.0 (CH3).
Macrocycle 7d
Glassy solid; yield: 12 mg (15% of a 10:1 macrocycle–cyclodimer
mixture).
1H NMR: d = 8.53 (d, 4J = 1.6 Hz, 1 H, Ar¢H-2), 8.18 (dd, 3J1 = 7.9
Hz, 4J2 = 1.6 Hz, 2 H, Ar¢H-4), 8.15 [s, 1 H, CH(triazole)], 8.10 [s,
4
1 H, CH(triazole)], 8.06 (d, J = 2.5 Hz, 1 H, ArH-2), 7.94 (dd,
3
3J1 = 8.8 Hz, 4J2 = 2.5 Hz, 1 H, ArH-6), 7.75 (d, J = 8.8 Hz, 1 H,
MALDI-TOF: m/z [M + Na]+ calcd for C66H94N6O9Na: 1137.70;
found: 1137.80.
ArH-5), 7.49 (t, 3J = 7.9 Hz, 1 H, Ar¢H-5), 5.38–5.26 (m, 4 H, CH2),
4.90 (m, 2 H, 3-CH), 0.94 (s, 6 H, 19-CH3), 0.89 (m, 6 H, 21-CH3),
0.60 (s, 3 H, 18-CH3), 0.58 (s, 3 H, 18-CH3).
Macrocycle 10a
White foam; yield: 8 mg (20%).
MALDI-TOF: m/z [M – 2N2 + H]+ calcd for C68H90ClN2O8:
1097.60; found: 1097.12.
1H NMR: d = 7.65 [s, 2 H, CH(triazole)], 5.46–5.04 (m, 4 H, CH2),
4.56 (m, 2 H, 3-CH), 3.90 (m, 2 H, 12-CH), 0.98 (s, 6 H, 19-CH3),
0.69 (d, 3J = 6.3 Hz, 6 H, 21-CH3), 0.65 (s, 6 H, 18-CH3).
MALDI-TOF: m/z [M + Na]+ calcd for C54H82N6O6: 933.62; found:
933.59.
Macrocycle 7e
Colorless solid; yield: 19 mg (18%); mp 192–195 °C (dec.).
1H NMR: d = 8.50 (d, 4J = 1.6 Hz, 1 H, Ar¢H-2), 8.18 (dd, 3J1 = 7.7
Hz, 4J2 = 1.6 Hz, 2 H, Ar¢H-4), 8.14 [s, 2 H, CH(triazole)], 8.05 (t,
4J = 1.9 Hz, 1 H, ArH-2), 7.90 (dd, 3J1 = 8.1 Hz, 4J2 = 2.0 Hz, 2 H,
ArH-4), 7.70 (t, 3J = 8.3 Hz, 1 H, ArH-5), 7.49 (t, 3J = 7.7 Hz, 1 H,
Ar¢H-5), 5.31 (m, 4 H, CH2), 4.93 (m, 2 H, 3-CH), 3.93 (m, 2 H, 12-
CH), 0.93 (m, 12 H, 2 CH3), 0.58 (s, 6 H, 18-CH3).
13C NMR: d = 174.1 (CO), 165.5 (CO), 144.4 [C(triazole)], 137.9
(ArC-5), 133.7 (Ar¢C-4), 131.5 131.2, (Ar¢C-1,5), 121.9 [CH(triaz-
ole)], 120.4 (ArC-4), 112.1 (ArC-2), 75.5 (3-CH), 72.9 (12-CH),
57.3, 48.3, 46.7, 46.4, 41.8, 35.8, 34.8, 34.7, 34.1, 33.6, 30.7, 30.6,
28.8, 27.4, 26.8, 26.5, 25.9, 25.6, 24.9, 23.5, 23.0, 17.3, 12.6.
Macrocycle 10b
White solid; yield: 11 mg (25%); mp 128–130 °C.
1H NMR: d = 7.69 [s, 2 H, CH(triazole)], 5.30–5.00 (m, 10 H,
CH2,CH), 0.96 (d, 3J = 6.8 Hz, 6 H, 21-CH3), 0.84 (s, 6 H, 19-CH3),
0.64 (s, 6 H, 18-CH3).
MALDI-TOF: m/z [M + H]+ calcd for C58H87N6O8: 995.64; found:
995.76.
Anal. Calcd for C58H86N6O8: C, 69.99; H, 8.71; N, 8.44. Found: C,
69.76; H, 8.90; N, 8.52.
MALDI-TOF: m/z [M + Na]+ calcd for C68H90N6O10Na: 1173.66;
found: 1173.86.
Anal. Calcd for C68H90N6O10: C, 70.93; H, 7.88; N, 7.30. Found: C,
70.83; H, 8.17; N, 7.03.
Acknowledgment
We are grateful to the Russian Foundation for Basic Research
(grants 08-03-91308-INDa and 07-03-00619a) for financial sup-
port.
Macrocycle 8a
Colorless solid; yield: 6 mg (9% of a 10:1 macrocycle–cyclodimer
mixture).
1H NMR: d = 8.63 (d, 4J = 1.5 Hz, 1 H, ArH-2), 8.19 (dd, 3J1 = 7.6
Hz, 4J2 = 1.6 Hz, 2 H, ArH-4), 7.58 [s, 2 H, CH(triazole)], 7.40 (t,
3J = 7.6 Hz, 1 H, ArH-5), 5.20 (s, 4 H, CH2), 4.95 (m, 2 H, 3-CH),
4.30 (m, 4 H, CH2), 2.29 (t, 3J = 7.7 Hz, 4 H, CH2), 0.95 (s, 6 H, 19-
CH3), 0.90 (d, 3J = 6.4 Hz, 6 H, 21-CH3), 0.63 (s, 6 H, 18-CH3).
MALDI-TOF: m/z [M + Na]+ calcd for C72H106N6O8Na: 1205.80;
found: 1205.80.
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Macrocycle 8b
White solid; yield: 9 mg (12% of a 10:1 macrocycle–cyclodimer
mixture).
1H NMR: d = 8.63 (d, 4J = 1.6 Hz, 1 H, ArH-2), 8.19 (dd, 3J1 = 7.8
Hz, 4J2 = 1.7 Hz, 2 H, ArH-4), 7.59 [s, 2 H, CH(triazole)], 7.50 (t,
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MALDI-TOF: m/z [M + Na]+ calcd for C71H104N6O8Na: 1191.69;
found: 1191.73.
Synthesis 2009, No. 15, 2605–2615 © Thieme Stuttgart · New York

PAPER
Copper-Catalyzed [1,3]-Dipolar Cycloadditions
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Synthesis 2009, No. 15, 2605–2615 © Thieme Stuttgart · New York