Conversion of macrocyclic polyamines into carbon-substituted derivatives. Synthesis of derivatives of 1,5,9-triazacyclododecane-2-carbonitrile

Full text of DOI:10.1021/jo951637h

J . Org. Chem. 1996, 61, 1847-1849
1847
Notes
R-cyanohydroxylamine 4 in 75% yield.5 Reduction of
compound 4 with TiCl3 in the presence of ammonium
acetate as buffer gave the corresponding protected R-cy-
anoamine 5 in 98% yield.6 Although similar sequences
of oxidation, cyanide addition, and reduction have been
used previously to convert simple acyclic and cyclic
secondary amines into R-cyanoamines,5 it is noteworthy
that this procedure can also be used to synthesize
macrocyclic derivatives. This observation indicates that
macrocyclic nitrones, R-cyano hydroxylamines, and R-cy-
anoamines are stable enough to serve as useful interme-
diates in synthesis. It is also noteworthy that other
methods for synthesizing simple R-substituted secondary
amines failed to yield carbon-substituted derivatives of
1,5,9-triazacyclododecane.7 For example, various at-
tempts to monometalate and functionalize N-nitrosamine
6 and carbamate 7 were unsuccessful.
We did not expect the cyano group to survive the
vigorous procedures required for hydrolyzing (4-meth-
ylphenyl)sulfonamides under acidic conditions, so we
attempted to deprotect compound 5 by using reductive
methods. Unfortunately, treatment with sodium in am-
monia effected reductive decyanation to give 1,5,9-
triazacyclododecane (2) in 70% yield,8 while milder
reductants such as aluminum amalgam,9 SmI2,10 and
calcium in ammonia11 left the protected R-cyanoamine 5
unchanged.
Con ver sion of Ma cr ocyclic P olya m in es in to
Ca r bon -Su bstitu ted Der iva tives. Syn th esis
of Der iva tives of
1,5,9-Tr ia za cyclod od eca n e-2-ca r bon itr ile
Philippe Brunet*,1 and J ames D. Wuest
De´partement de Chimie, Universite´ de Montre´al,
Montre´al, Que´bec H3C 3J 7, Canada
Received September 6, 1995
In tr od u ction
A large number of macrocyclic polyamines have been
synthesized as ligands for the chelation of metals.2 They
are widely used in coordination chemistry, and their
complexes have found many applications as diagnostic
agents for magnetic resonance imaging, therapeutic
conjugates, sequestering agents, mimetics of metalloen-
zymes, and reagents for inducing NMR shifts and relax-
ation. Substituted derivatives of simple macrocyclic
polyamines are typically prepared by functionalizing
atoms of nitrogen, and few carbon-substituted derivatives
are available.3 In this paper, we show that carbon-
substituted macrocyclic polyamines can be made directly
from the unsubstituted parent compounds. Specifically,
we describe the preparation of derivatives of 1,5,9-
triazacyclododecane-2-carbonitrile (1) starting from 1,5,9-
triazacyclododecane (2).
To facilitate deprotection, we therefore decided to
prepare the corresponding Boc-protected R-cyanoamine
8 from dicarbamate 9 by a similar series of reactions.
Bicyclic formamidinium salt 10 was prepared from 1,5,9-
triazacyclododecane (2) in two steps by the published
method12 and was then converted into monoprotected
N-benzyl derivative 11 by basic hydrolysis in 99% yield.
NR2 R2N
NR2 R2N
R1
N
R1
N
CN
1 (R1 = R2 = H)
2 (R1 = R2 = H)
3 (R1 = H, R2 = Ts)
6 (R1 = R2 = NO)
7 (R1 = R2 = Boc)
9 (R1 = H, R2 = Boc)
11 (R1 = CH2Ph, R2 = H)
12 (R1 = CH2Ph, R2 = Boc)
+
N
N
4 (R1 = OH, R2 = Ts)
5 (R1 = H, R2 = Ts)
8 (R1 = H, R2 = Boc)
13 (R1 = OH, R2 = Boc)
N
R
10 (R = CH2Ph)
Subsequent treatment of compound 11 with excess di-
tert-butyl dicarbonate in the presence of triethylamine
then afforded dicarbamate 12 in 99% yield. Hydro-
genolysis of compound 12 provided the required dicar-
Resu lts a n d Discu ssion
Bis[(4-methylphenyl)sulfonamide] 3 was prepared in
68% yield by the selective ditosylation of 1,5,9-triazacy-
clododecane (2).4 Tungstate-catalyzed oxidation of com-
pound 3 with H2O2, followed by addition of excess KCN
to the intermediate nitrone, then provided protected
(5) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe,
S. J . Org. Chem. 1990, 55, 1736. Murahashi, S.-I.; Shiota, T. Tetra-
hedron Lett. 1987, 28, 6469.
(6) For similar reductions, see: Murahashi, S.-I.; Kodera, Y. Tet-
rahedron Lett. 1985, 26, 4633.
(1) Fellow of the Ministe`re de l’EÄ ducation du Que´bec (1985-1990).
(2) Kimura, E. Tetrahedron 1992, 48, 6175. Bianchi, A.; Micheloni,
M.; Paoletti, P. Coord. Chem. Rev. 1991, 110, 17. Lindoy, L. F.
The Chemistry of Macrocyclic Ligand Complexes; Cambridge University
Press: Cambridge, 1989.
(3) For recent references, see: Aston, K. W.; Henke, S. L.; Modak,
A. S.; Riley, D. P.; Sample, K. R.; Weiss, R. H.; Neumann, W. L.
Tetrahedron Lett. 1994, 35, 3687. Begley, M. J .; Crombie, L.; Haigh,
D.; J ones, R. C. F.; Osborne, S.; Webster, R. A. B. J . Chem. Soc., Perkin
Trans. 1 1993, 2027. McMurry, T. J .; Brechbiel, M.; Wu, C.; Gansow,
O. A. Bioconjugate Chem. 1993, 4, 236. Kimura, E.; Kurogi, Y.;
Shionoya, M.; Shiro, M. Inorg. Chem. 1991, 30, 4524. Helps, I. M.;
Parker, D.; J ankowski, K. J .; Chapman, J .; Nicholson, P. E. J . Chem.
Soc., Perkin Trans. 1 1989, 2079.
(7) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109. Enders, D.;
Pieter, R.; Renger, B.; Seebach, D. Org. Synth. 1978, 58, 113.
(8) For similar observations, see: Ogura, K.; Shimamura, Y.; Fujita,
M. J . Org. Chem. 1991, 56, 2920. Yue, C.; Royer, J .; Husson, H.-P. J .
Org. Chem. 1990, 55, 1140. Bunnelle, W. H.; Shevlin, C. G. Tetrahedron
Lett. 1989, 30, 4203. Thies, H.; Scho¨nenberger, H.; Qasba, P. K.
Tetrahedron Lett. 1965, 163.
(9) Kurzmeier, H.; Schmidtchen, F. P. J . Org. Chem. 1990, 55, 3749.
Arzeno, H. B.; Kemp, D. S. Synthesis 1988, 32.
(10) Ku¨nzer, H.; Stahnke, M.; Sauer, G.; Wiechert, R. Tetrahedron
Lett. 1991, 32, 1949.
(11) Hwu, J . R.; Chua, V.; Schroeder, J . E.; Barrans, R. E., J r.;
Khoudary, K. P.; Wang, N.; Wetzel, J . M. J . Org. Chem. 1986, 51, 4731.
(12) Weisman, G. R.; Vachon, D. J .; J ohnson, V. B.; Gronbeck, D.
A. J . Chem. Soc., Chem. Commun. 1987, 886.
(4) For
a similar procedure, see: Weighardt, K.; Tolksdorf, I.;
Herrmann, W. Inorg. Chem. 1985, 24, 1230.
0022-3263/96/1961-1847$12.00/0 © 1996 American Chemical Society

1848 J . Org. Chem., Vol. 61, No. 5, 1996
Notes
with H2O, and dried in vacuo to give a mixture of di- and
trisulfonamides.
bamate 9 in quantitative yield. Although the synthesis
of dicarbamate 9 from 1,5,9-triazacyclododecane (2)
requires five steps, it proceeds in 85% overall yield, and
no chromatographic purifications are needed.
Volatiles were removed from the combined aqueous phases
by evaporation under reduced pressure, and the residue was
subjected to ion-exchange chromatography (Dowex 2-X8, OH-
form, H2O/CH3OH). Solvent was removed from the eluent by
evaporation under reduced pressure, and the residue was
extracted with CHCl3. Removal of volatiles from the extracts
left a residue of recovered 1,5,9-triazacyclododecane (2; 0.186 g,
1.09 mmol).
Initial attempts to convert dicarbamate 7 into pro-
tected R-cyano hydroxylamine 13 by tungstate-catalyzed
oxidation with H2O2 were unsuccessful. However, we
eventually discovered that the use of H2O2 and excess
sodium tungstate, followed by the addition of KCN and
enough aqueous HCl to attain a pH of 7, gave compound
13 in 65% yield. Similarly, reduction of R-cyano hy-
droxylamine 13 to R-cyano amine 8 also required modi-
fication of the standard conditions. After extensive study,
we found that the use of TiCl3 without buffer in degassed
CH3OH/H2O provided R-cyanoamine 8 in quantitative
yield. Deprotection using trifluoroacetic acid in CH2Cl2
then gave the tris(trifluoroacetate) salt of 1,5,9-triaza-
cyclododecane-2-carbonitrile (1), which was used without
further purification in subsequent reactions analogous
to those of 1,5,9-triazacyclododecane (2) itself. For
example, condensation of unsubstituted compound 2 with
formamidinium salts is known to give tricyclic orthoform-
amide 14a .13 Similarly, neutralization of the tris(triflu-
oroacetate) salt of nitrile 1 and subsequent condensation
with formamidinium acetate provided cyanoorthoform-
amide 14b stereospecifically.14
The solid mixture of di- and trisulfonamides was separated
by flash chromatography (silica, CHCl3 (97%)/CH3OH (2%)/
N(C2H5)3 (1%)). This provided 1,5-bis[(4-methylphenyl)sulfonyl]-
1,5,9-triazacyclododecane (3; 1.51 g, 3.15 mmol, 68% based on
unrecovered 1,5,9-triazacyclododecane) as a colorless solid. An
analytically pure sample was obtained by recrystallization from
CH3OH: mp 169°C; IR (CHCl3) 3400, 1337, 1159 cm-1; 1H NMR
3
(400 MHz, CDCl3) δ 1.70 (tt, 4H, J ) 6.6, 5.4 Hz), 1.89 (quint,
3
3
2H, J ) 6.9 Hz), 2.42 (s, 6H), 2.66 (t, 4H, J ) 5.4 Hz), 3.16 (t,
3
3
3
4H, J ) 6.9 Hz), 3.18 (t, 4H, J ) 6.6 Hz), 7.30 (d, 4H, J ) 7.9
Hz), 7.65 (d, 4H, 3J ) 7.9 Hz); 13C NMR (100 MHz, CDCl3) δ
21.4, 24.1, 27.5, 43.9, 45.3, 46.2, 127.3, 129.6, 135.3, 143.2; MS
(EI) m/ e 480, 324. Anal. Calcd for C23H33N3O4S2: C, 57.59; H,
6.93. Found: C, 57.15; H, 6.93.
1-H yd r oxy-5,9-b is[(4-m et h ylp h en yl)su lfon yl]-1,5,9-t r i-
a za cyclod od eca n e-2-ca r bon itr ile (4). A solution of 1,5-bis-
[(4-methylphenyl)sulfonyl]-1,5,9-triazacyclododecane (3; 1.22 g,
2.54 mmol) in a mixture of THF (17 mL) and H2O (7 mL) was
stirred at 0 °C and treated with Na2WO4‚2H2O (0.042 g, 0.13
mmol) and 30% aqueous H2O2 (0.61 mL, 6.0 mmol). The
resulting mixture was kept at 25 °C for 18 h, cooled to 0 °C, and
treated with KCN (0.307 g, 4.71 mmol) and 4 N aqueous HCl
(0.91 mL, 3.6 mmol). The mixture was kept at 25 °C for 30 h,
and then volatiles were removed by evaporation under reduced
pressure. H2O (30 mL) was added to the residue, and the
basicity was adjusted to pH 8-9 by the addition of 2 N aqueous
NaOH. The resulting mixture was extracted with CH2Cl2, and
volatiles were removed from the combined extracts by evapora-
tion under reduced pressure. Flash chromatography (silica,
CHCl3 (99%)/CH3OH (1%)) of the residue provided 1-hydroxy-
5,9-bis[(4-methylphenyl)sulfonyl]-1,5,9-triazacyclododecane-2-
carbonitrile (4; 0.987 g, 1.90 mmol, 75%) as a colorless solid.
Recrystallization from benzene/CH2Cl2 yielded an analytically
H
N
N
N
R
14a (R = H)
14b (R = CN)
Con clu sion s
pure sample: mp 192-193 °C; IR (KBr) 3470, 1330, 1150 cm-1
;
Diprotected 1,5,9-triazacyclododecane 3 can be con-
verted into carbon-substituted cyano derivative 5 in 73%
overall yield by a simple procedure involving oxidation
with Na2WO4/H2O2, addition of KCN, and subsequent
reduction with TiCl3. A similar procedure transformed
diprotected 1,5,9-triazacyclododecane 9 into diprotected
1,5,9-triazacyclododecane-2-carbonitrile 8 in 65% overall
yield. This strategy promises to be a useful general
method for the direct conversion of macrocyclic polyamines
into carbon-substituted derivatives that would otherwise
not be readily available.
1H NMR (400 MHz, CDCl3) δ 1.50-1.65 (m, 1H), 1.76-1.87 (m,
1H), 2.00-2.11 (m, 2H), 2.18-2.29 (m, 1H), 2.30-2.42 (m, 1H),
2.44 (s, 3H), 2.45 (s, 3H), 2.79-2.94 (m, 2H), 2.95-3.18 (m, 5H),
3.21-3.37 (m, 3H), 4.01 (dd, 3J ) 11.5, 3.7 Hz, 1H), 5.38 (bs,
1H), 7.31-7.36 (m, 4H), 7.65-7.67 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 21.4, 21.4, 23.2, 26.2, 30.4, 42.5, 42.5, 46.3, 47.6, 54.7,
56.1, 117.0, 127.0, 127.3, 129.8, 129.9, 133.3, 135.4, 143.7, 144.1;
MS (FAB) m/ e 521, 494, 365; HRMS (FAB) calcd for
C
24H32N4O5S2 + H 521.1892, found 521.1916.
5,9-Bis[(4-m eth ylp h en yl)su lfon yl]-1,5,9-tr ia za cyclod od e-
ca n e-2-ca r b on it r ile (5). A solution of 1-hydroxy-5,9-bis-
[(4-methylphenyl)sulfonyl]-1,5,9-triazacyclododecane-2-carboni-
trile (4; 0.485 g, 0.932 mmol) and ammonium acetate (1.75 g,
22.7 mmol) in a deoxygenated mixture of THF (14 mL) and H2O
(4.2 mL) was stirred at 25 °C under N2 and treated dropwise
with a solution of TiCl3 (0.878 g, 5.69 mmol) in deoxygenated
H2O (7.5 mL). The mixture became deep green and then deep
blue, and it was stirred at 25 °C for 22 h. A second portion of
TiCl3 (0.451 g, 2.92 mmol) in H2O (3.8 mL) was added, and the
mixture was stirred at 25 °C for an additional 9 h. The mixture
was then made strongly basic by the addition of 10% aqueous
NaOH, diluted with H2O, and extracted with CH2Cl2. Evapora-
tion of volatiles from the combined extracts left a residue of 5,9-
bis[(4-methylphenyl)sulfonyl]-1,5,9-triazacyclododecane-2-car-
bonitrile (5; 0.461 g, 0.913 mmol, 98%) as a colorless waxy solid.
Flash chromatography (silica, CHCl3 (99%)/CH3OH (1%)) pro-
Exp er im en ta l Section
Tetrahydrofuran (THF) was dried by distillation from the
sodium ketyl of benzophenone, and N(C2H5)3 was dried by
distillation from CaH2. Other commercial reagents were used
without further purification. Flash chromatography was per-
formed in the normal way.15
1,5-Bis[(4-m eth ylp h en yl)su lfon yl]-1,5,9-tr ia za cyclod od e-
ca n e (3). A solution of 1,5,9-triazacyclododecane (2; 0.984 g,
5.74 mmol) and NaOH (0.284 g, 7.10 mmol) in H2O (4.3 mL)
was stirred at 0 °C and treated dropwise with a solution of (4-
methylphenyl)sulfonyl chloride (2.05 g, 10.8 mmol) in ether (7.2
mL). The resulting mixture was stirred at 0 °C for 1 h. The
precipitated solid was separated by filtration, washed thoroughly
vided an analytically pure sample: IR (CHCl3) 1342, 1160 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.00 (bs, 1H), 1.49-1.68 (m, 2H),
1.71-1.83 (m, 2H), 1.95-2.08 (m, 1H), 2.44 (s, 3H), 2.45 (s, 3H),
2.50-2.62 (m, 1H), 2.66-2.75 (m, 2H), 2.91-2.98 (m, 2H), 3.07-
3.26 (m, 3H), 3.30-3.38 (m, 2H), 3.40-3.48 (m, 1H), 3.76 (dd,
3J ) 11.7, 2.6 Hz, 1H), 7.31 (d, 3J ) 8.3 Hz, 2H), 7.34 (d, 3J )
(13) Erhardt, J . M.; Grover, E. R.; Wuest, J . D. J . Am. Chem. Soc.
1980, 102, 6365. Erhardt, J . M.; Wuest, J . D. J . Am. Chem. Soc. 1980,
102, 6363.
(14) For a detailed description of the synthesis, characterization,
and reactions of orthoformamide 14b and related structures, see:
Brunet, P.; Wuest, J . D. J . Org. Chem., in press.
3
8.3 Hz, 2H), 7.64 (d, J ) 8.3 Hz, 2H), 7.67 (d, 3J ) 8.3 Hz, 2H);
(15) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
13C NMR (75.4 MHz, CDCl3) δ 21.4, 21.4, 23.4, 26.8, 32.6, 42.6,

Notes
J . Org. Chem., Vol. 61, No. 5, 1996 1849
42.7, 43.9, 45.2, 46.4, 47.3, 120.0, 127.1, 127.4, 129.7, 129.8,
133.6, 136.0, 143.3, 143.9; MS (FAB) m/ e 505, 478, 351; HRMS
(FAB) calcd for C24H32N4O4S2 + H 505.1943, found 505.1962.
Anal. Calcd for C24H32N4O4S2: C, 57.12; H, 6.39. Found: C,
57.08; H, 6.53.
treated with KCN (309 mg, 4.75 mmol) and enough 4 N aqueous
HCl (0.9 mL) to lower the pH to 7. After 22 h, the mixture was
concentrated by partial evaporation under reduced pressure,
15% aqueous NaOH was added to adjust the basicity to pH 8-9,
and the mixture was extracted with CH2Cl2. Volatiles were
removed from the combined extracts by evaporation under
reduced pressure, and the residue was purified by flash chro-
matography (silica, CHCl3 (98%)/CH3OH (2%)). This yielded bis-
(1,1-dimethylethyl) 8-cyano-9-hydroxy-1,5,9-triazacyclododecane-
1,5-dicarboxylate (13; 639 mg, 1.55 mmol, 65%) as a colorless
solid: IR (CHCl3) 3414, 1692 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.46 (s, 9H), 1.47 (s, 9H), 1.85-2.38 (m, 5H), 2.75 (ddd, J )
13.3, 10.1, 3.2 Hz, 1H), 3.07-3.42 (m, 9H), 3.51 (dt, J ) 14.2,
4.3 Hz, 1H), 3.77 (m, 1H), 5.07 (bs, 1H); 13C NMR (75.4 MHz,
CDCl3) δ 25.3, 25.8, 28.2, 28.3, 29.9, 42.7, 43.4, 45.9, 46.4, 54.7,
56.5, 79.6, 80.0, 116.9, 156.3, 156.3; MS (FAB) m/ e 413, 386,
313, 286, 213; HRMS (FAB) calcd for C20H36N4O5 + H 413.2764,
found 413.2758.
1-(P h en ylm eth yl)-1,5,9-tr ia za cyclod od eca n e (11). A so-
lution of 5-(phenylmethyl)-5,9-diaza-1-azoniabicyclo[7.3.1]tridec-
1(13)-ene (10; 1.94 g, 5.51 mmol)12 and NaOH (7.1 g, 180 mmol)
in a mixture of C2H5OH (192 mL) and H2O (64 mL) was heated
at reflux for 16 h. After partial evaporation under reduced
pressure, more H2O was added and the mixture was extracted
with CH2Cl2. Removal of volatiles from the combined extracts
by evaporation under reduced pressure left a residue of 1-(phen-
ylmethyl)-1,5,9-triazacyclododecane (11; 1.43 g, 5.47 mmol, 99%)
as a colorless solid. Recrystallization from benzene/CH2Cl2
provided an analytically pure sample: mp 192-193 °C; IR
(CHCl3) 3348 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.65-1.77 (m,
3
3
6H), 2.52 (t, J ) 5.9 Hz, 4H), 2.70 (t, J ) 5.5 Hz, 4H), 2.84 (t,
3J ) 5.5 Hz, 4H), 3.13 (bs, 2H), 3.49 (s, 2H), 7.21-7.41 (m, 5H);
13C NMR (75.4 MHz, CDCl3) 25.7, 26.4, 46.9, 49.2, 52.4, 57.2,
126.6, 127.9, 128.8, 139.0; MS (FAB) m/ e 262; HRMS (FAB)
calcd for C16H27N3 + H 262.2283, found 262.2273.
Bis(1,1-d im eth yleth yl) 8-Cya n o-1,5,9-tr ia za cyclod od e-
ca n e-1,5-d ica r boxyla te (8). A solution of bis(1,1-dimethyl-
ethyl) 8-cyano-9-hydroxy-1,5,9-triazacyclododecane-1,5-dicar-
boxylate (13; 530 mg, 1.3 mmol) in deoxygenated CH3OH (20
mL) was added under Ar to a stirred solution of TiCl3 (620 mg,
4.0 mmol) in deoxygenated H2O (3 mL). The deep blue solution
was kept at 25 °C for 15 min and was then poured into a
separatory funnel containing cold CH2Cl2 (50 mL) and 15%
aqueous NaOH (2 mL). The contents were shaken vigorously,
the funnel was opened periodically to admit air, and 15%
aqueous NaOH was added occasionally to maintain a strongly
basic solution. When the blue color had disapeared and an
abundant white precipitate had formed, the aqueous phase was
extracted with CH2Cl2. The phases were separated by centrifu-
gation, and volatiles were removed from the combined organic
extracts by evaporation under reduced pressure. This yielded
bis(1,1-dimethylethyl) 8-cyano-1,5,9-triazacyclododecane-1,5-di-
carboxylate (8; 510 mg, 1.3 mmol, 100%) as a colorless oil: IR
(CHCl3) 3324, 1682 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.40 (s,
9H), 1.41 (s, 9H), 1.61-1.95 (m, 3H), 1.95-2.11 (m, 1H), 2.34
-2.48 (m, 1H), 2.51-2.62 (m, 1H), 2.99-3.55 (m, 12H); 13C NMR
(75.4 MHz, CDCl3) δ 26.4, 27.6, 28.2, 28.3, 32.3, 43.4, 44.3, 44.4,
46.0, 46.5, 47.2, 79.2, 79.7, 120.0, 156.0, 156.0; MS (FAB) m/ e
397, 370, 297, 170; HRMS (FAB) calcd for C20H36N4O4 + H
397.2815, found 397.2841.
Bis(1,1-d im eth yleth yl) 9-(P h en ylm eth yl)-1,5,9-tr ia za cy-
clod od eca n e-1,5-d ica r boxyla te (12). A solution of 1-(phen-
ylmethyl)-1,5,9-triazacyclododecane (11; 1.43 g, 5.47 mmol) and
N(C2H5)3 (1.34 g, 13.2 mmol) in dry THF (50 mL) was stirred at
25 °C under dry N2, and a solution of di-tert-butyl dicarbonate
(2.75 g, 12.6 mmol) in THF (10 mL) was added. The mixture
was kept at 25 °C for 6 d, and then 15% aqueous NaOH (20
mL) was added. After 18 h, the mixture was concentrated by
partial evaporation under reduced pressure, diluted with H2O,
and extracted with CH2Cl2. Removal of volatiles from the
combined extracts by evaporation under reduced pressure left
a residue of pure bis(1,1-dimethylethyl) 9-(phenylmethyl)-1,5,9-
triazacyclododecane-1,5-dicarboxylate (12; 2.49 g, 5.39 mmol,
99%) as a pale yellow oil: IR (CHCl3) 1690 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.43 (s, 18H), 1.78 (quint, 3J ) 6.4 Hz, 4H), 1.90
3
3
3
(quint, J ) 7.0 Hz, 2H), 2.41 (t, J ) 6.4 Hz, 4H), 3.32 (t, J )
6.4 Hz, 4H), 3.36 (t, 3J ) 7.0 Hz, 4H), 3.51 (s, 2H), 7.19-7.31
(m, 5H); 13C NMR (75.4 MHz, CDCl3) δ 26.7, 27.3, 28.4, 43.6,
44.9, 50.1, 58.7, 79.1, 126.8, 128.1, 128.8, 139.2, 156.1; MS (EI)
m/ e 462, 370, 270, 170; HRMS (EI) calcd for C26H43N3O4 + H
462.3332, found 462.3338. Anal. Calcd for C26H43N3O4: C,
65.11; H, 9.46. Found: C, 65.69; H 9.23.
Tr is(tr iflu or oacetate) Salt of 1,5,9-Tr iazacyclododecan e-
2-ca r bon itr ile (1). A solution of bis(1,1-dimethylethyl) 8-cyano-
1,5,9-triazacyclododecane-1,5-dicarboxylate (8; 336 mg, 0.847
mmol) in CH2Cl2 (3 mL) was stirred at 0 °C and treated with
CF3COOH (3 mL). The cooling bath was removed, the mixture
was stirred for 15 min, and then volatiles were removed by
evaporation under reduced pressure. This yielded the tris-
(trifluoroacetate) salt of 1,5,9-triazacyclododecane-2-carbonitrile
(1; 454 mg, 0.843 mmol, 100%) as a colorless hygroscopic oil that
was used in subsequent reactions without further purification:
1H NMR (300 MHz, D2O) δ 1.55-1.72 (m, 1H), 1.73-2.19 (m,
4H), 2.41-2.53 (m, 1H), 2.82-3.30 (m, 10H), 3.76 (dd, 3J ) 11.2,
2.7 Hz, 1H); 13C NMR (75.4 MHz, D2O) δ 21.4, 24.2, 28.9, 42.8,
43.7, 45.8, 46.4, 46.5, 49.8, 117.1 (q, 1J CF ) 290 Hz), 119.6, 162.9
Bis(1,1-d im et h ylet h yl) 1,5,9-Tr ia za cyclod od eca n e-1,5-
d ica r boxyla te (9). A mixture of bis(1,1-dimethylethyl) 9-(phen-
ylmethyl)-1,5,9-triazacyclododecane-1,5-dicarboxylate (12; 2.6 g,
5.6 mmol) and 10% Pd on charcoal (5.0 g) in absolute C2H5OH
(80 mL) was stirred at 25 °C for 4 d under H2 (6 atm). The
catalyst was separated by filtration, and volatiles were removed
by evaporation under reduced pressure. This left a residue of
bis(1,1-dimethylethyl) 1,5,9-triazacyclododecane-1,5-dicarbox-
ylate (9; 2.1, 5.6 mmol, 100%) as a colorless solid. Flash
chromatography (silica, CHCl3 (95%)/CH3OH (5%)) provided an
analytically pure sample: mp 92-93 °C; IR (CHCl3) 3430, 1693
1
3
cm-1; H NMR (400 MHz, CDCl3) δ 1.43 (s, 18H), 1.77 (tt, J )
3
3
5.9, 5.5 Hz, 4H), 1.88 (quint, J ) 6.9 Hz, 2H), 2.67 (t, J ) 5.5
Hz, 4H), 3.28 (t, J ) 6.9 Hz, 4H), 3.31 (t, J ) 5.9 Hz, 4H); 13
NMR (100 MHz, CDCl3) δ 27.5, 28.0, 28.4, 45.9, 46.3, 46.9, 79.1,
C
3
3
2
(q, J CF ) 36.5 Hz).
156.3; MS (EI) m/ e 372, 272, 172; HRMS (EI) calcd for
C
C
19H37N3O4 + H 372.2862, found 372.2903. Anal. Calcd for
19H37N3O4: C, 61.43; H, 10.04. Found: C, 61.25; H, 10.26.
Bis(1,1-d im eth yleth yl) 8-Cya n o-9-h yd r oxy-1,5,9-tr ia za -
Ack n ow led gm en ts. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
and the Ministe`re de l’EÄ ducation du Que´bec for financial
support. In addition, we thank Professor Peter Beak
and Professor Shun-Ichi Murahashi for helpful dis-
cussions.
cyclod od eca n e-1,5-d ica r boxyla te (13). A solution of bis(1,1-
dimethylethyl) 1,5,9-triazacyclododecane-1,5-dicarboxylate (9;
883 mg, 2.38 mmol) in THF (33 mL) was stirred at 25 °C and
treated successively with Na2WO4‚2H2O (913 mg, 2.77 mmol),
H2O (37 mL), and 30% aqueous H2O2 (0.62 mL, 6.0 mmol). The
resulting mixture was kept at 25 °C for 19 h and was then
J O951637H