A simple, regioselective synthesis of 1,4-bis(tert-butoxycarbonylmethyl)-tetraazacyclododecane

Article abstract of DOI:10.1021/jo026436+

A convenient synthetic route to 1,4-bis(tert-butoxycarbonylmethyl)tetraazacyclododecane (cyclen) (1) with high yield and excellent regioselectivity is described. Compound 1 reacted with a range of functionalized alkyl halides under two reaction conditions to give mono-N-alkylated 1,4-bis(tert-butoxycarbonylmethyl)tetraazacyclododecane (2-9) in good yield.

Full text of DOI:10.1021/jo026436+

A Sim p le, Regioselective Syn th esis of
lie on the same cyclen molecule are attracting consider-
able attention. Recently, Bornhop reported that a tumor-
specific agent and an energy absorbing/transmitting
chromophore were conjugated to one cyclen framework;
the resulting lanthanide complex not only afforded
ligand-specific cell targeting in vivo and in vitro, but also
provided the real-time intraoperative fluorescence that
1
,4-Bis(ter t-bu toxyca r bon ylm eth yl)-
tetr a a za cyclod od eca n e
Cong Li and Wing-Tak Wong*
Department of Chemistry and Open Laboratory of Chemical
Biology of the Institute of Molecular Technology for Drug
Discovery and Synthesis, The University of Hong Kong,
Pokfulam Road, Hong Kong, P. R. China
10
correlates with anatomic imaging. Although a number
1
1
of methods for the mono-N-alkylation and tri-N-alkyl-
ation12 of cyclen have been developed, relatively fewer
strategies for bis-alkylation are available. Selective bis-
alkylations of cyclen have all been achieved via tempo-
wtwong@hkucc.hku.hk
1
3
14
rary diprotection by tosyl, methyl, and phosphoryl
Received September 11, 2002
groups,15 carbamates moieties, silicon intermediates,
16
17
1
8
and oxamide groups. However, nearly all these proce-
dures only allow 1,7-bis-functionalization except refs 13b
and 18, and no good direct 1,4-bis-N-alkylation of cyclen
has been reported to our knowledge. In our previous
reports, a direct method for the preparation of mono-N-
alkylated cyclam and cyclen was described.19 Using this
procedure, a Tb complex of cyclam containing three
chelated carboxylic acids and a crown ether was found
to signal [Na ] and [K ] with luminescence lifetime as
output.20 As part of a continuous effort in this area, we
report a convenient procedure for directly introducing
tert-butoxycarbonylmethyl groups (precursor of carboxylic
acid) to the two neighboring N-substituted positions of
cyclen in high yield and with excellent regioselectivity.
Abstr a ct: A convenient synthetic route to 1,4-bis(tert-
butoxycarbonylmethyl)tetraazacyclododecane (cyclen) (1)
with high yield and excellent regioselectivity is described.
Compound 1 reacted with a range of functionalized alkyl
halides under two reaction conditions to give mono-N-
alkylated 1,4-bis(tert-butoxycarbonylmethyl)tetraazacyclo-
dodecane (2-9) in good yield.
+
+
1
,4,7,10-Tetraazacyclododecane (cyclen)-based multi-
dentate ligands are very useful chelating agents for
lanthanide(III) ions. The resulting complexes show high
thermodynamic and kinetic stability in aqueous solution
and have been widely used as magnetic resonance
1
imaging (MRI) contrast agents (CAs) (Gd complexes);
diagnostic-therapeutic radio-pharmaceuticals carrying
(
6) (a) Aime, S.; Botta, M.; Fasano, M.; Terreno, E. Chem. Soc. Rev.
9
0
2
radionuclides such as Y; luminescence probes and
1998, 27, 19. (b) Corsi, D. M.; Elst, L. V.; Muller, R. N.; van Bekkum,
H.; Peter, J . A. Chem. Eur. J . 2001, 7, 64. (c) Aime, S.; Botta, M.; Crich,
S. G.; Giovenzana, G.; Palmisano, G.; Sisti, M. Chem. Commun. 1999,
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D.; Senanayake, K.; Williams, J . A. G. J . Chem. Soc., Perkin Trans. 2
998, 2129.
3
4
labels containing Eu and Tb; RNA cleavers (La) and
catalysts5 (Y, La, and Yb). In these complexes, three
pendant chelating moieties, especially the carboxylate at
the N-substituted positions, are utilized for strong lan-
thanide chelation and hence give rise to neutral metal
complexes. The remaining N-substituted position of cy-
1
1
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6
clen can be derivatized to improve tissue selectivity,
7
7,8
enhance light-harvesting efficiency, or sense pH value,
(
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8
9
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novel systems in which two different functional groups
(
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1) (a) Alexander, V. Chem. Rev. 1995, 95, 273. (b) Caravan, P.;
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(
(
Volkert, W. A.; Hoffman, T. J . Chem. Rev. 1999, 99, 2269. (c)
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1
993, 58, 6895. (e) Brechbiel, M. W.; Pippin, C. G.; McMurry, T. J .;
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Chem. Rev. 1999, 185-186, 297. (d) Aoki, S.; Kawatani, H.; Goto, T.;
Kimura, E.; Shiro, M. J . Am. Chem. Soc. 2001, 123, 1123.
(
4) (a) Amin, S.; Morrow, J . R.; Lake, C. H.; Churchill, M. R. Angew.
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1995, 185. (b) Kovacs, Z.; Sherry, A. D. Synthesis 1997, 759.
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H. J . Chem. Soc., Chem. Commun. 1995, 1233.
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Le Mest, Y.; Handel, H. J . Chem. Soc., Perkin Trans. 1 1999, 3499.
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(20) Li, C.; Wong, W. T. Chem. Commum. 2002, 2034.
Chem., Int. Ed. Engl. 1994, 33, 773. (b) Morrow, J . R.; Amin, S.; Lake,
C. H.; Churchill, M. R. Inorg. Chem. 1993, 32, 4566. (c) Amin, S.; Voss,
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(
5) (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl.
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P. A., Ed.; Blackie Academic & Professional: London, 1998; p 262.
1
1
0.1021/jo026436+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/25/2003
2
956
J . Org. Chem. 2003, 68, 2956-2959

TABLE 1. Effect of Solven t a n d Ba se on th e Yield a n d
Regioselectivity of 1,4-Bis(ter t-bu toxyca r bon ylm eth yl)-
1
,4,7,10-tetr a a za cyclod od eca n e (1)
1
,4/1,7-bis-
b
yield (%)
substituted
entry conditionsa
base
tris bis mono
cyclen
c
e
1
2
3
4
5
6
CHCl3, rt free
CHCl3, rt pyridine
14 55
11 63
15 57
∼8
∼5
∼6
∼2
∼8
∼7
>99
f
e
>99
d
e
CHCl3, rt K2CO3
>99
CHCl3, rt triethylaminef
6
84
>99
e
DMF, rt
triethylaminef 13 61
4.3
3.2
MeOH, rt triethylaminef 23 46
a
The two starting materials in all reactions were in the ratio
of cyclen/tert-butyl bromoacetate ) 1:2 and conducted at room
b
temperature; reaction time ranged from 6 to 8 h. Isolated yield
c
of purified product after flash chromatography. The ratio was
1
F IGURE 1. Plots of the yield (b) and the ratio (9) of 1,4/1,7-
bis(tert-butoxycarbonylmethyl)-substituted cyclen as a function
determined by 400 MHz H NMR and flash chromatography
results.24
d
Five equivalents of K2CO3 was used. 1,7-Bis(tert-
e
f
of concentrations of starting material (cyclen) in CHCl
3
(rt,
butoxycarbonylmethyl)cyclen was not detected. 10 equiv of tri-
ethylamine or pyridine was used.
2
.0 equiv of tert-butyl bromoacetate, 10 equiv of triethylamine).
SCHEME 1. Syn th esis of
,4-Bis(ter t-bu toxyca r bon ylm eth yl)-1,4,7,10-
tetr a a za cyclod od eca n e (1)
conformation in a less polar and aprotic solvent such as
chloroform at room temperature.23 After the first alkyl-
ation, the two 4-position N-H would be logically intra-
annular and H-bonded to the intraannular N lone pairs
of the alkylated and the 7-position nitrogen. Thus, only
the extraannular lone pairs of the two nitrogens at
1
4
-position are available for further alkylation. To confirm
Previously, Kruper found that the regioselectivity of
the alkylation of polyazamacrocycles was dependent on
both the steric hindrance of electrophiles and solvent
systems.21 For this reason, tert-butyl bromoacetate as the
precursor of pendant carboxylic acid was chosen to react
with cyclen in chloroform at room temperature in the
presence of 10 equiv of triethylamine. 1,4-Bis(tert-butoxy-
carbonylmethyl)-1,4,7,10-tetraazacyclododecane (1) was
isolated in good yield after flash chromatography. The
the effect of base, comparative studies between the
absence and the presence of various bases were per-
formed in chloroform (entries 1-4, Table 1). Among the
auxiliary bases examined, triethylamine gave the highest
2 3
yield. The use of K CO or pyridine led to a remarkable
decrease in the yield of 1, with the yield never exceeding
65%. It is also worthy of mention that the regioselectivity
was kept constant regardless of the base used in the
chloroform solvent system.
1
,7-bis-substituted product was not detected (Scheme 1).
Selective mono-N-alkylation of 1,4-bis(tert-butoxycar-
bonylmethyl)-1,4,7,10-tetraazacyclododecane (1) is an-
other key step in the preparation of unsymmetrical bis-
functionalized ligands, which initially requires a functional
pendant group filling one of the remaining two N-
substituted positions of 1, while the other one is left for
another alkylating agent. To investigate the selectivity
and yields of 1 to various alkylation agents, especially
Surprisingly, this excellent regioselectivity for 1,4-
substituted product 1 was kept constant in the cyclen’s
concentration range of 10-120 mM (Figure 1). To clarify
the effect of the solvent and auxiliary base on the yield
of this reaction, experiments under different conditions
were conducted. The following observations were sum-
3
marized from the data shown in Table 1: The CHCl /
triethylamine system afforded the most satisfactory
result. Regioselectivity remained independent of the
concentrations of the starting materials, and at the same
time, the yield of bis-substituted product only has a
moderate decrease when the concentration of cyclen
added exceeded 60 mM. The effect of various solvents on
the yield and regioselectivity was obvious, with chloro-
form being the solvent of choice (entries 4-6, Table 1).
The use of weakly polar and aprotic solvents such as
chloroform is preferable to polar, aprotic solvents such
as DMF and polar, protic solvents such as methanol,
which lead to substantial decreases in yield and regiose-
lectivity by promoting proton transfer.22 We speculated
that this high regioselectivity in chloroform can be
explained by the following assertion. The 12-membered
cyclen ring has a strongly preferred square [3333]
those with functional groups that have been widely used
in previous works,6
,9,11,21
electrophiles with pendant crown
ethers, aza-crown ethers, quinaldine, carbon chain, and
â-D-glucopyranoside were prepared, respectively. Accord-
ing to our earlier work on the preparation of mono-N-
alkylated cyclam and cyclen,19 treatment of 1 with
stoichiometric electrophiles 2a -9a in acetonitrile with
2 3
5.0 equiv of K CO at 55-60 °C gave different results
under these conditions, producing mono-N-alkylation
products in adequate yields only with the “less active”
halides 7a -9a (Table 2). Using “active” alkyl halides such
as allyl halide, benzyl halides, and R-halo carbonyl groups
produced predominantly undesired bis-substituted com-
(23) Glass, R. S. Conformational Analysis of Medium-Sized Hetero-
cycles; VCH: New York, 1988; pp 122-123.
(
24) The 1,4- and 1,7-bis-substituted products can be easily exam-
13
ined by the C NMR spectral signal of the cyclen carbons; the
1,7-bis-substituted adduct displays two carbon signals for the 16
carbons in the macrocycle indicating a D2h symmetry, whereas 1,4-
bis-substituted adduct displays four carbon signals indicating C2v
symmetry.
(
21) Kruper, W. J ., J r.; Rudolf, P. R.; Langhoff, C. A. J . Org. Chem.
993, 58, 3869.
22) Reichardt, C.Solvents and Solvent Effects in Organic Chemistry,
nd ed.; VCH: New York, 1988; pp 121-208.
1
(
2
J . Org. Chem, Vol. 68, No. 7, 2003 2957

TABLE 2. Rea ction of “Less-Active” Alk yla tion Agen ts
TABLE 3. Rea ction of “Active” Alk yla tion Agen ts 2a -6a
w ith 1,4-Bis(ter t-bu toxyca r bon ylm eth yl)-1,4,7,10-
tetr a a za cyclod od eca n e (1)
7
a -9a w ith 1,4-Bis(ter t-bu toxyca r bon ylm eth yl)-1,4,7,10-
tetr a a za cyclod od eca n e (1)
pounds. Even when 1.5 equiv of 1 with these halides was
used, the yields of mono-substituted products showed no
obvious improvement. However, under milder reaction
conditions at room temperature and the use of KHCO
instead of K CO , the reaction led to a considerable
3
2
3
increase in the yield of monoalkylation product. A stoi-
chiometric amount of 1 and “active” halides 2a -6a
provided satisfactory yields of mono-N-alkylation prod-
ucts 2-6 (77-87%) (Table 3). As can be seen in Tables 2
and 3, in addition to the reactivity, steric hindrance of
eletrophiles is thought to be another important factor
affecting the yield of mono-N-alkylation product 2-9. For
features such as high yield, operational convenience, and
cost economy. This methodology allows efficient alkyla-
tion, with a wide range of electrophiles, especially for
sterically hindered macromolecules and bioactive-mole-
cules.
“less active” halides 7a -9a , the introduction of a less
sterically hindered bromide gave rise to mono-N-alkyla-
tion products in better yields. Compound 7a with a long
carbon chain gave the highest yield at 91% (entry 1, Table
Exp er im en ta l Section
Gen er a l E xp er im en t a l P r oced u r es. Unless otherwise
stated, starting materials were obtained from commercial sup-
pliers and used as received. Flash chromatograpy was performed
using silica gel (70-230 mesh) and aluminum oxide 90 active
2
). However, the “active” halides 2a -6a showed dramati-
cally different behavior. The steric hindrance facilitated
the preparation of monoalkylation products 2-6, bulky
electrophiles with macrocycles and quinoline such as 3a ,
neutral (70-230 mesh). Powdered K
2
CO
to use and stored under Ar. H (300 and 400 MHz) and C (75
and 100 MHz) NMR spectra were measured in CDCl with SiMe
δ 0 ppm) as an internal standard. H NMR data are recorded
3
was predried just prior
1
13
5
a , and 6a (entry 2, 4, and 5, Table 3) gave the yields all
above 80%. The least sterically hindered halide 4a with
an allyl group displayed high propensity for the bis-N-
substituted products; even under very mild reaction
conditions the yield of bis-N-alkylation product was
maintained at about 30%.
3
4
1
(
1
3
as follows: chemical shift (δ). For C NMR spectra, the data
are given as follows: chemical shift (δ). FT-IR spectra were
recorded on dry KBr pellets; mass spectra (MS) were obtained
at a fast atom bombardment source (FABMS) and an electron
spray ionization source (ESIMS). All ESIMS spectra were carried
out using MeOH as the solvent.
In conclusion, we developed a straightforward method
for the preparation of 1,4-bis(tert-butoxycarbonylmethyl)-
1
,4-Bis(ter t-bu toxyca r bon ylm eth yl)-1,4,7,10-tetr a a za cy-
clod od eca n e (1). 1,4,7,10-Tetraazacyclododecane (cyclen) (400
mg, 2.3 mmol) was dissolved in 20 mL of anhydrous CHCl , and
0.0 equiv of triethylamine (2.3 g, 23.2 mmol) was added to the
solution. tert-Butyl bromoacetate (2 equiv, 904.8 mg, 4.6 mmol)
dissolved in 10 mL of CHCl was added dropwise to the
1
,4,7,10-tetraazacyclododecane (1) in high yields and with
excellent regioselectivity. Two general reaction conditions
have been put forward for the synthesis of mono-N-
alkylation of 1 with functionalized “active” and “less-
active” halides. Furthermore, those accounts illustrate
good potential since both the selective bis-alkylation and
mono-alkylation of tetraazamacrocycles derivatives are
in a single step without use of unnecessary protecting
groups. Generally, these methods provide the introduc-
tion of different functional groups to the two remaining
neighboring N-substituted positions of 1 with attractive
3
1
3
vigorously stirred solution. The addition lasted for about 1 h,
and the solution continued to react for another 6 h at room
temperature. CHCl was evaporated, the transparent oil was
3
dissolved in 10 mL of water, and the pH was adjusted to 11-12
by addition of 40% (w/v) NaOH solution. The mixture was
extracted with CHCl
combined and dried over Na
3
(4 × 15 mL), and the CHCl
3
extracts were
SO . The combined extracts were
2
4
2
958 J . Org. Chem., Vol. 68, No. 7, 2003

dried in vacuo, and the residue was loaded onto an aluminum
oxide (neutral, 70-230 mesh) column. The column was eluted
oxide (CH
2
Cl
2
/MeOH ) 100:2.5, R
f
) 0.25) to give 6 as a colorless
) δ 3.77-
3.49, 3.35, 3.27, 3.18-2.72, 1.42, 1.40; C NMR (100 MHz,
CDCl
1
oil: yield 183.7 mg (87%); H NMR (400 MHz, CDCl
3
1
3
with a mixture of CH
product was collected, and solvent was removed to give 1 as a
white powder solid: yield 778 mg (84%); H NMR (400 MHz,
2
Cl
2
/MeOH ) 100:3 (v/v) (R ) 0.35), the
f
3
) δ 170.8, 170.6, 169.9, 81.6, 71.2, 70.8, 70.7, 70.6, 70.4,
70.2, 69.9, 69.6, 57.9, 56.7, 51.9, 51.8, 51.2, 49.7, 49.6, 49.5, 49.2,
48.4, 47.3, 46.7, 28.3, 28.2; IR (KBr, cm ) 2976, 1732, 1717,
1651, 1636, 1506, 1458, 1362, 1242, 1151, 1109; ESIMS m/z
1
1
3
-1
CDCl
CDCl
3
) δ 3.32, 2.98-2.96, 2.89-2.87, 1.41; C NMR (100 MHz,
3
) δ 170.1, 81.6, 53.4, 51.1, 49.9, 46.5, 46.1, 28.2; IR (KBr,
-
1
+
+
cm ) 2976, 1732, 1715, 1636, 1559, 1457, 1167; ESIMS m/z
704.5 (M + H) ; HRFABMS m/z 704.4802 (M + H) [calcd for
+
+
+
4
01.3 (M + H) ; HRFABMS m/z 401.3130 (M + H) [calcd for
C
34
H
66
N
5
O
10 (M + H) , 704.4810].
+
20 41 4 4
C H N O (M +H) 401.3128].
Gen er a l Meth od for th e P r ep a r a tion of 7-9. To the
Gen er a l Meth od for th e P r ep a r a tion of 2-6. To the
appropriate electrophiles 7a -9a (0.30 mmol) dissolved in 10.0
mL of acetonitrile was added dropwise a mixture of 1.0 equiv of
1,4-bis(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclodode-
appropriate electrophiles 2a -6a (0.30 mmol) dissolved in 10.0
mL of acetonitrile was added dropwise a mixture of 1.0 equiv of
1
,4-bis(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclodode-
cane 1 (120.0 mg, 0.30 mmol) and 5.0 equiv of KHCO (208.5
mg, 1.5 mmol) in 40 mL of anhydrous acetonitrile under a N
cane 1 (120.0 mg, 0.30 mmol) and 5.0 equiv of K
1.5 mmol) in 40 mL of anhydrous acetonitrile under a N
2 3
CO (207.0 mg,
3
2
atmosphere for ∼30 min. The mixture was stirred at 55-60 °C
for ∼8-10 h, the solution was filtered under reduced pressure,
and the extract was dried in vacuo to give the crude products
7-9.
7-(1-Un d e ca n ol)-1,4-b is(t er t -b u t oxyca r b on ylm e t h yl)-
1,4,7,10-tetr a a za cyclotetr a d eca n e (7). The reaction was car-
ried out as described in the general procedure. The crude product
was purified by flash chromatography on aluminum oxide
2
atmosphere for ∼30 min. The mixture was stirred at room
temperature for ∼4-8 h, and the solution was filtered under
reduced pressure and dried in vacuo to give the crude products
2
-6.
7
-Ben zyl-1,4-b is(ter t-b u t oxyca r b on ylm et h yl)-1,4,8,11-
tetr a a za cyclotetr a d eca n e (2). The reaction was carried out
as described in the general procedure. The crude product was
purified by flash chromatography on aluminum oxide (EtOAc/
(EtOAc/MeOH ) 100:8, R
f
) 0.25) to give 7 as a colorless oil:
1
MeOH ) 100:8, R
f
) 0.20) to give 2 as a colorless oil: yield 122.2
mg (83%); H NMR (400 MHz, CDCl ) δ 7.33-7.23, 3.69, 3.36,
.12, 3.05-2.54, 1.44, 1.36; C NMR (100 MHz, CDCl ) δ 170.6,
yield 155.6 mg (91%); H NMR (400 MHz, CDCl ) δ 3.56, 3.31,
3
1
3.23, 3.05-2.94, 2.93-2.70, 2.51-2.46, 1.51, 1.40 (s, 20H), 1.22;
3
1
3
13C NMR (100 MHz, CDCl ) δ 170.4, 169.7, 81.5, 81.4, 62.7, 58.4,
3
1
5
2
4
C
3
3
69.7, 138.4, 129.6, 128.6, 127.8, 81.6, 81.5, 62.9, 58.9, 51.8, 51.5,
58.0, 51.3, 51.1, 50.6, 50.3, 49.3, 48.7, 48.0, 47.8, 32.7, 29.5, 29.4,
0.4, 50.1, 49.9, 49.6, 48.5, 48.0, 47.6, 28.3, 28.2; IR (KBr, cm-1
29.3, 28.2, 28.1, 27.3, 27.0, 25.7; IR (KBr, cm-1) 2973, 2857, 1735,
)
+
980, 1726, 1452, 1362, 1254, 1215, 1151, 731, 700; ESIMS m/z
1457, 1376, 1160; ESIMS m/z 571.5 (M + H) ; HRFABMS m/z
+
+
571.4792 (M + H)
+
[calcd for C
H
31 63
N O (M + H) 571.4798].
+
91.4 (M + H) ; HRFABMS m/z 491.3597 (M + H) [calcd for
4
5
+
7-(2,3,4,6-Tetr a a cetyl-1-(2-eth oxyl)-D-glu cop yr a n osid e)-
27
H
47
N
4
O
4
(M + H) , 491.3597].
-(2-Meth ylqu in olin e)-1,4-bis(ter t-bu toxyca r bon ylm eth -
1
,4-b is(ter t-b u t oxyca r b on ylm et h yl)-1,4,7,10-t et r a a za cy-
7
clotetr a d eca n e (8). The reaction was carried out as described
in the general procedure. The crude product was purified by flash
yl)-1,4,8,11-tetr a a za cyclotetr a d eca n e (3). The reaction was
carried out as described in the general procedure. The crude
product was purified by flash chromatography on aluminum
chromatography on silica gel (CH
to give 8 as a colorless oil: yield 197.6 mg (85%); H NMR (400
MHz, CDCl ) δ 5.20, 4.96, 4.83, 4.44, 4.22-4.17, 4.04-3.98,
2
Cl
2
/MeOH ) 100:7, R ) 0.25)
f
1
oxide (EtOAc/MeOH ) 100:10, R
f
) 0.25) to give 3 as a colorless
oil: yield 138.1 mg (85%); H NMR (400 MHz, CDCl ) δ 8.11,
.00, 7.76, 7.66, 7.53, 7.50, 4.03, 3.36, 3.16, 3.07-3.03, 2.90-
1
3
3
3
.90-3.83, 3.64-3.60, 3.57-3.50, 3.32, 3.28, 2.97, 2.90-2.57,
8
2
1
8
2
8
13
1
3
3
1.98, 1.93, 1.91, 1.88, 1.38, 1.37; C NMR (100 MHz, CDCl ) δ
.79, 1.44, 1.25; C NMR (100 MHz, CDCl
3
) δ 170.6, 169.5,
1
7
70.5, 170.4, 170.1, 169.9, 169.4, 169.2, 100.9, 81.7, 81.6, 72.8,
2.0, 71.3, 68.4, 67.8, 61.9, 58.1, 56.6, 51.7, 51.3, 50.9, 50.8, 49.5,
58.7, 147.6, 136.6, 129.7, 129.1, 127.6, 127.2, 126.5, 121.6, 81.5,
1.4, 64.1, 58.6, 51.5, 50.7, 50.4, 49.9, 49.6, 48.1, 48.0, 47.7, 28.1,
-1
-
1
49.1, 48.5, 48.1, 47.5, 28.2, 28.0, 20.8, 20.5; IR (KBr, cm ) 2971,
1753, 1732, 1636, 1559, 1457, 1365, 1227, 1158, 1038; ESIMS
8.0; IR (KBr, cm ) 2965, 2847, 1717, 1559, 1457, 1259, 1151,
+
13, 752; ESIMS m/z 542.3 (M + H) ; HRFABMS m/z 542.3728
+
+
+
+
m/z 775.4 (M + H) ; HRFABMS m/z 775.4344 (M + H) [calcd
48 5 4
(M + H) [calcd for C30H N O (M + H) , 542.3706].
+
for C36
7
63 4
H N O14 (M + H) 775.4341].
7
-Allyl-1,4-bis(ter t-bu t oxyca r bon ylm et h yl)-1,4,8,11-t et -
-(2-(Eth oxym eth yl)-15-cr ow n -5)-1,4-bis(ter t-bu toxyca r -
r a a za cyclotetr a d eca n e (4). The reaction was carried out as
described in the general procedure. The crude product was
bon ylm eth yl)-1,4,7,10-tetr a a za cyclotetr a d eca n e (9). The
reaction was carried out as described in the general procedure.
The crude product was purified by flash chromatography on
purified by flash chromatography on silica gel (CH
100:19, R ) 0.30) to give 4 as a colorless oil: yield 101.7 mg
77%); H NMR (400 MHz, CDCl ) δ 5.88-5.84, 5.19-5.16, 3.35,
2 2
Cl /MeOH
)
(
3
1
4
1
f
1
aluminum oxide (CH
as a colorless oil: yield 168.5 mg (83%); H NMR (400 MHz,
2
Cl
2
/MeOH ) 100:2.5, R
f
) 0.20) to give 9
3
1
.27, 3.20, 3.10-2.60, 1.44, 1.43; 1 C NMR (100 MHz, CDCl
3
3
) δ
70.6, 169.7, 134.6, 119.0, 81.7, 60.7, 58.6, 51.5, 50.6, 50.2, 49.4,
1
3
CDCl
(100 MHz, CDCl
70.5, 70.4, 70.3, 70.2, 70.1, 69.9, 69.5, 68.5, 58.4, 56.5, 51.5, 51.2,
3
) δ 3.71-3.42, 3.34, 3.26, 3.07-2.54, 1.41, 1.39; C NMR
-1
3
) δ 170.6, 169.7, 81.6, 81.5, 78.2, 71.1, 70.6,
8.9, 48.6, 48.1, 47.9, 28.3, 28.2; IR (KBr, cm ) 3094, 2971, 1732,
+
715, 1653, 1457, 1369, 1254, 1156; ESIMS m/z 441.3 (M + H) ;
-1
+
50.8, 49.5, 49.1, 48.1, 48.0, 47.5, 28.3, 28.2; IR (KBr, cm ) 2971,
2922, 2868, 1732, 1716, 1653, 1557, 1457, 1260, 1157, 1115;
HRFABMS m/z 441.3439 (M + H) [calcd for C23
H) , 441.3441].
45 4 4
H N O (M +
+
+
+
ESIMS m/z 677.5 (M + H) ; HRFABMS m/z 677.4702 (M + H)
7
-(N-Acetyla za -15-cr ow n -5)-1,4-bis(ter t-bu toxyca r bon yl-
+
[calcd for C33
H
65
N
4
O
10 m/z (M + H) 677.4701.
m eth yl)-1,4,8,11-tetr a a za cyclotetr a d eca n e (5). The reaction
was carried out as described in the general procedure. The crude
product was purified by flash chromatography on aluminum
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the Hong Kong Research Grants
Council and the University of Hong Kong. This work is
also supported by an Area of Excellence Scheme of
the University Grants Committee (Hong Kong). C.L.
acknowledges the receipt of a postgraduate student-
ship administered by the University of Hong Kong.
oxide (CH
2
Cl
2
/MeOH ) 100:2.5, R
f
) 0.25) to give 5 as a colorless
) δ 3.74,
.63-3.54, 3.51, 3.42, 3.33, 3.24, 3.03-3.01, 2.91-2.75, 1.40,
1
oil: yield 164.3 mg (83%); H NMR (400 MHz, CDCl
3
3
1
8
4
1
1
3
3
.39; C NMR (100 MHz, CDCl ) δ 170.9, 170.6, 169.9, 81.7,
1.6, 71.6, 70.5, 70.3, 70.1, 69.9, 69.4, 57.9, 56.9, 51.8, 51.6, 51.3,
9.8, 49.7, 49.6, 49.2, 49.1, 47.3, 28.3, 28.2; IR (KBr, cm-1) 2977,
732, 1715, 1657, 1637, 1506, 1458, 1362, 1242, 1154, 1108;
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization data of halides 3a , 5a , 6a , 8a , and
+
+
ESIMS m/z 660.4 (M + H) ; HRFABMS m/z 660.4547 (M + H)
+
[calcd for C32
H
62
N
5
O
9
(M + H) , 660.4548].
1
13
9
2
a ; H NMR, C NMR, and ESI-MS spectra of compounds
-9. This material is available free of charge via the Internet
7
-(N-Acetyla za -18-cr ow n -6)-1,4-bis(ter t-bu toxyca r bon yl-
m eth yl)-1,4,8,11-tetr a a za cyclotetr a d eca n e (6). The reaction
was carried out as described in the general procedure. The crude
product was purified by flash chromatography on aluminum
at http://pubs.acs.org.
J O026436+
J . Org. Chem, Vol. 68, No. 7, 2003 2959