Regioselective N-functionalization of tetraazacycloalkanes

Article abstract of DOI:10.1021/jo050306u

Bisaminal type compounds obtained by condensation of pyruvic aldehyde with the suitable open-chain tetraamine followed by cyclization with either dibromoethane or dibromopropane can be regioselectively quaternized by a wide range of alkylating agents. Removal of the bisaminal bridge yields the monosubstituted tetraazamacrocycle or bismacrocycle. Further functionalization allows the preparation of bifunctional ligands or trisubstituted macrocycles. The structure of six compounds was solved by X-ray diffraction, and the unexpected results are rationalized according to the molecular modeling calculations.

Full text of DOI:10.1021/jo050306u

Regioselective N-Functionalization of Tetraazacycloalkanes
Fre´de´ric Boschetti,† Franck Denat,† Enrique Espinosa,† Alain Tabard,† Yves Dory,‡ and
Roger Guilard*,†
Universite´ de Bourgogne, Laboratoire d’Inge´nierie Mole´culaire pour la Se´paration et les Applications des
Gaz, LIMSAG UMR 5633, Faculte´ des Sciences Gabriel, 6 boulevard Gabriel, 21100 Dijon, France, and
Laboratoire de Synthe`se Supramole´culaire, Departement de Chimie, Institut de Pharmacologie,
Universite´ de Sherbrooke, 3001, 12e avenue Nord, Sherbrooke (Que´bec), Canada J1H 5N4
limsag@u-bourgogne.fr
Received February 17, 2005
Bisaminal type compounds obtained by condensation of pyruvic aldehyde with the suitable open-
chain tetraamine followed by cyclization with either dibromoethane or dibromopropane can be
regioselectively quaternized by a wide range of alkylating agents. Removal of the bisaminal bridge
yields the monosubstituted tetraazamacrocycle or bismacrocycle. Further functionalization allows
the preparation of bifunctional ligands or trisubstituted macrocycles. The structure of six compounds
was solved by X-ray diffraction, and the unexpected results are rationalized according to the
molecular modeling calculations.
Introduction
bifunctional chelating agents (BFCs or BCAs).9 Indeed,
macrocyclic amines bearing two kinds of functional
groups, for both metal coordination and immobilization
on a solid support or on a monoclonal antibody, have
attracted special attention in recent years. Mono-N-
functionalization is difficult to accomplish without re-
sorting to the use of a large excess of the initial unsub-
stituted macrocycle. Different methods involve the pro-
tection of three secondary amines with protecting groups
such as tert-butyloxycarbonyl (Boc)10 or tosyl groups
(Ts),11 especially for preparing bismacrocycles. Another
approach is to take advantage of the coordinating proper-
ties of the cyclic amine for the discrimination of one
nitrogen atom over the three other ones. To this end,
boron, phosphoryl, trimethylsilyl entities as well as metal
carbonyls (M(CO)6 where M ) Cr, Mo, or W) have been
utilized.12,13 However, all of these methods are based on
protection/deprotection strategies starting from the costly
Cyclic tetraamines have known a growing interest
owing to their coordination properties and their wide
range of applications.1-7 The affinity of the macrocycle
toward a specific guest, a metallic cation in most cases,
might be tuned by varying the nature, the number, and
the relative positions of the pendant arms on the nitrogen
atoms. N-Functionalization with four identical pendant
arms is straightforward. However, the preparation of only
partially functionalized macrocycles is more synthetically
demanding.8 There is a significant interest in such
ligands since further functionalization makes access to
* To whom correspondence should be addressed. Fax: +33 380 396
117.
† Universite´ de Bourgogne.
‡ Universite´ de Sherbrooke.
(1) Haines, R. I. Rev. Inorg. Chem. 2001, 21, 165-205.
(2) Meyer, M.; Dahaoui-Gindrey, V.; Lecomte, C.; Guilard, R. Coord.
Chem. Rev. 1998, 178-180, 1313-1405.
(3) Wainwright, K. P. Coord. Chem. Rev. 1997, 166, 35-90.
(4) Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R. L. Chem.
Rev. 1995, 95, 2529-2586.
(9) Liu, S.; Edwards, D. S. Bioconjugate Chem. 2001, 12, 7-34.
(10) Brande`s, S.; Gros, C.; Denat, F.; Pullumbi, P.; Guilard, R. Bull.
Soc. Chim. Fr. 1996, 133, 65-73.
(5) Reichenbach Klinke, R.; Konig, B. J. Chem. Soc., Dalton Trans.
2002, 121-130.
(11) Ciampolini, M.; Fabbrizzi, L.; Perotti, A.; Poggi, A.; Seghi, B.;
Zanobini, F. Inorg. Chem. 1987, 26, 3527-3533.
(6) Kimura, E. Tetrahedron 1992, 48, 6175-6217.
(7) Merbach, A. E., Toth, E., Eds. The Chemistry of Contrast Agents
in Medical Magnetic Resonance Imaging; John Wiley & Sons: New
York, 2001.
(12) Yaouanc, J. J.; Le Bris, N.; Le Gall, G.; Clement, J. C.; Handel,
H.; Des Abbayes, H. J. Chem. Soc., Chem. Commun. 1991, 206-
207.
(13) Gardinier, I.; Roignant, A.; Oget, N.; Bernard, H.; Yaouanc, J.
J.; Handel, H. Tetrahedron Lett. 1996, 37, 7711-7714.
(8) Denat, F.; Brande`s, S.; Guilard, R. Synlett 2000, 561-574.
10.1021/jo050306u CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/09/2005
7042
J. Org. Chem. 2005, 70, 7042-7053

Regioselective N-Functionalization of Tetraazacycloalkanes
SCHEME 1
initial unsubstituted macrocycle. These drawbacks
prompted us to develop new methods in regard to the
two important concepts in synthetic efficiency: selectivity
and atom economy.14 The new syntheses should proceed
in a minimum number of steps with high yields, as broad
as possible regarding the nature of the macrocycle and
the pendant arms. We have recently reported in a short
communication the synthesis of selectively mono-N-
benzylated cyclam and 1,4,7,10-tetraazacyclotridecane
by using a bisaminal moiety acting both as a template
and as a protecting group.15 In this work, we describe
the synthesis of various monofunctionalized macrocy-
cles and bismacrocycles. The selectivity of the reaction
of two linear tetraamines with pyruvic aldehyde, the
cyclization of the bisaminal intermediates with biselec-
trophilic reagents, and the quaternization of the pro-
tected macrocycles are discussed on the basis of X-ray
structure determinations and molecular modeling calcu-
lations.
compound 3 has been confirmed by a single-crystal X-ray
analysis (Figure 1a). The minor compound is the cis
isomer 4 in which the methyl group is connected to the
aminal type carbon located between the two tertiary
amines. The cis configuration of this compound is con-
firmed by NMR spectroscopy since the 13C NMR spec-
trum is temperature dependent.17-19 The condensation
of pyruvic aldehyde with N,N′-bis(3-aminopropyl)ethyl-
enediamine 2 gives the vic-trans isomer 5 as the major
compound when the reaction is performed in either
acetonitrile at 4 °C or ethanol at 4 °C, together with a
small amount (10%) of cis isomer 6. No trace of gem
isomers is observed.
The cyclization reaction of the different bisaminals
with dibromoethane or dibromopropane should yield
the corresponding bisaminal-protected macrocycle. In
fact, these protected cyclic tetraamines can be obtained
following a one-pot procedure without isolating the inter-
mediates (Scheme 2). Starting from the linear tetra-
amine 1 or 2, the condensation of pyruvic aldehyde is
performed in acetonitrile at 4 °C, and then K2CO3 and
the biselectrophilic reagent are added and the mixture
is refluxed for 2 days. Yields indicated in Scheme 2 are
the isolated yields starting from the linear tetraamine,
after purification of compounds 7-10 by column chro-
matography.
Results and Discussion
Synthesis. First, we have studied the condensation
of pyruvic aldehyde with linear tetraamines 1 and 2
(Scheme 1). Several isomers can be theoretically ex-
pected, compounds of vic type and more fused sytems
called gem forms in which one of the two aminal-type
carbon atoms is common to the three cycles.16,17 Because
of the dissymmetry of pyruvic aldehyde, two different
gem-type compounds exist depending on the relative
position of the methyl group. In addition, different
stereoisomers can be formed for each of these compounds.
The hydrogen atom and the methyl group of the bridge
may lie either on the same side or the opposite sides of
the average plane defined by the four nitrogen atoms,
noted in the text as cis or trans isomers, respectively.
The composition of the mixtures has been determined on
the basis of the NMR spectra.
Obviously, the best results are observed starting from
tetraamine 1, the protected macrocycles 7 and 8 being
obtained in 69% and 68% yield, respectively. Bisaminal-
protected macrocycles 9 and 10 have been prepared from
the linear tetraamine 2 in 22% and 25% overall yield,
respectively. A mixture of the compound 9 and the cis
isomer 8 is obtained in 29% after chromatography and
1
the ratio has been determined by integration of the H
NMR resonances. Compound 9 can be isolated as a pure
compound after washing the mixture with cold acetone
and its structure was solved by X-ray diffraction (Figure
1b).
The reaction of N,N′-bis(2-aminoethyl)-1,3-propanedi-
amine 1 with pyruvic aldehyde in acetonitrile at 4 °C
quantitatively yields a mixture of two gem-cis isomers,
3 and 4, in a 4:1 ratio. The structure of the major
Bisaminal adducts can be deprotected to release the
corresponding free macrocycle, i.e., cyclam or 13aneN4.
However, the interest of the method does not lie in the
synthesis of the macrocycle itself after removal of the
bisaminal bridge. In this regard, pyruvic aldehyde does
not present a significant advantage over butanedione, for
(14) Trost, B. M. Acc. Chem. Res. 2002, 35, 695-705.
(15) Boschetti, F.; Denat, F.; Espinosa, E.; Guilard, R. Chem.
Commun. 2002, 312-313.
(16) Herve´, G.; Bernard, H.; Le Bris, N.; Le Baccon, M.; Yaouanc,
J.-J.; Handel, H. Tetrahedron Lett. 1999, 40, 2517-2520.
(17) Herve´, G.; Le Bris, N.; Bernard, H.; Yaouanc, J.-J.; Des Abbayes,
H.; Handel, H. J. Organomet. Chem. 1999, 585, 259-265.
(18) Kolinski, R. A.; Riddell, F. G. Tetrahedron Lett. 1981, 22, 2217-
2220.
(19) Jazwinski, J.; Kolinski, R. A. Tetrahedron Lett. 1981, 22, 1711-
1714.
J. Org. Chem, Vol. 70, No. 18, 2005 7043

Boschetti et al.
FIGURE 1. ORTEP views of (a) 3, (b) 9, (c) 11, and (d) 19 (hydrogen atoms are omitted for clarity; ellipsoids are shown at 50%
probability level).
SCHEME 2a
a Key: (i) pyruvic aldehyde, CH3CN, 4 °C; (ii) dibromoethane (n ) 0) or dibromoporpane (n ) 1), K2CO3, CH3CN, reflux.
example. Compared to glyoxal adducts, the bisaminal-
protected macrocycles obtained with pyruvic aldehyde are
less stable and the bridge can be removed under mild
experimental conditions to release the macrocycle, as in
the case of butanedione. Only the deprotection of com-
pound 9 failed, but this is not unexpected regarding
the very high stability of the similar trans cyclam/gly-
oxal adduct which cannot be deprotected even under very
harsh conditions.20 The principal advantage of pyruvic
aldehyde when compared to the two other R-carbonyl
compounds arises from its lower symmetry. Indeed, one
may take advantage of the presence of the bisaminal
moiety to perform selective mono-N-quaternization before
removal of the protecting bridge (Schemes 3 and 4).
It has to be noted that the quaternization occurs
selectively on the nitrogen atom linked to the aminal
carbon bearing the methyl group as evidenced by X-ray
structure determination of compounds 11 and 19 (Figure
1c,d). Consequently, only one isomer of the two possible
mono-N-functionalized 13aneN4 derivatives is obtained
after removal of the bisaminal bridge. Attempts to
quaternize analogous butanedione protected macrocycles
failed while quaternization of glyoxal cyclam adducts may
lead to a mixture of the mono- and the 1,7-disubstituted
compounds.20 Moreover, the bisaminal bridge cannot be
easily removed.
Various electrophilic reagents have been used and most
reactions have been performed starting from protected
macrocycle 7 (Schemes 3 and 4). The procedure has
also been applied for the preparation of bismacrocycles
(Scheme 5).
Most of the monofunctionalized 13aneN4 obtained
after removal of the bisaminal bridge were not pre-
(20) Kotek, J.; Hermann, P.; Vojtisek, P.; Rohovec, J.; Lukes, I.
Collect. Czech. Chem. Commun. 2000, 65, 243-266.
7044 J. Org. Chem., Vol. 70, No. 18, 2005

Regioselective N-Functionalization of Tetraazacycloalkanes
SCHEME 3
SCHEME 4
SCHEME 5
viously described in the literature. Attempts to isolate
monoester from 14 failed due to the reactivity of the ester
moiety, which can give the corresponding acid in the
conditions used for the deprotection (NaOH or HCl
aqueous solutions) and/or undergo lactamisation. Such
intramolecular cyclization of 1,8-diacetic acid cyclam has
already been reported.21,22 We have also observed that
cyclam monoester 26 synthesized by classical method
(reaction of ethylbromoacetate with a large excess of
cyclam) readily cyclizes to yield the novel bicyclic lactam
27 (Scheme 6 and Figure 2).
Many different procedures have been devised for the
synthesis of the benzylated cyclam 2012,23-26 and the
bismacrocycle 25,10,27 known as a highly potential anti-
(21) Chapman, J.; Ferguson, G.; Gallagher, J. F.; Jennings, M. C.;
Parker, D. J. Chem. Soc., Dalton Trans. 1992, 345-353.
(22) Helps, I. M.; Parker, D.; Chapman, J.; Ferguson, G. J. Chem.
Soc., Chem. Commun. 1988, 1094-1095.
J. Org. Chem, Vol. 70, No. 18, 2005 7045

Boschetti et al.
further functionalized by reaction with ethyl bromo-
acetate to yield compound 28 which is easily depro-
tected to give the novel triester 29 (Scheme 7). It has to
be noted that, unlike monoester 26, 29 does not un-
dergo any lactamisation reaction. A broad range of
valuable bifunctional chelating agents can be designed
starting from either the mono- or tri-N-functionalized
macrocycles that are easily prepared according to this
new method.
Discussion on the Formation and the Reactivity
of the Bisaminal Intermediates. It appears from the
experimental results reported herein as well as in the
literature that the condensation of a linear tetraamine
with a R-dicarbonyl compound, the cyclization of the
resulting bisaminal intermediate, the quaternization
reaction of the corresponding protected macrocycle, and
the removal of the bisaminal bridge are strongly de-
pendent on the nature of the tetraamine and the R-di-
carbonyl compound. Indeed, the yields of these different
reactions may range from 0 to 100% depending on the
precursors. To rationalize these experimental observa-
tions, we have undertaken molecular modeling studies.
These calculations, supported by X-ray structures, helped
us in better understanding the reactivity of these rigid
polycyclic bisaminal-type compounds.
First, we have investigated the condensation of N,N′-
bis(2-aminoethyl)-1,3-propanediamine 1 and N,N′-bis(3-
aminopropyl)ethylenediamine 2 with pyruvic aldehyde.
The energies of the different adducts, regarding the
orientation of the bisaminal bridge (gem or vic com-
pounds), the cis or trans configuration of the substituents
(H or Me) on the aminal carbons, the location of the
methyl group, as well as the relative orientation of the
lone pairs on the secondary amine type nitrogen atoms
have been initially calculated by semiempirical AM1
calculations.29 Then, the energies of the most stable
compounds have been refined by DFT/B3LYP/6.31 G*
calculations.29 To determine the reliability of this proce-
dure, the most stable geometries for the studied com-
pounds were calculated and the molecular conformations
were compared by overlay to the experimental structures
(Table 1).30 The accordance between the calculated and
the experimental geometrical parameters is high, the
root-mean square deviation (rmsd) being systematically
lower than 0.079 Å.
FIGURE 2. ORTEP view of 27 (hydrogen atoms are omitted
for clarity, ellipsoids are shown at 50% probability level).
SCHEME 6
HIV compound named JM3100 or AMD3100 in its fully
protonated form. However, the method described herein
is much more convenient for the synthesis of such com-
pounds. Glyoxal has already been used as a protecting
group for the synthesis of monobenzylcyclam20 as well
as JM3100.28 The authors added glyoxal to cyclam, the
quaternization step was then performed then the bisami-
nal bridge was removed by using hydroxylamine. How-
ever, the use of glyoxal both as a template and as a
protecting group has never been described before. More-
over, pyruvic aldehyde, which has never been used as a
template or as a protecting group, replaces glyoxal ad-
vantageously since the deprotection of the bisaminal ad-
duct is much easier. Butanedione is not convenient since
the bisaminal adduct does not undergo quaternization
(vide supra). In the case of the macrocycle 13aneN4, the
use of pyruvic aldehyde presents an additional advan-
tage, i.e., the control of the location of the N-substituent.
Indeed, two different N-functionalized macrocycles exist
because of the lack of symmetry of the cyclic amine. By
using this approach, only one out the two regioisomers
is obtained. This level of selectivity cannot be reached
via any of the classical methods including direct func-
tionalization or protection/deprotection sequences.
Finally, tri-N-functionalized tetraazacycloalkanes have
been prepared starting from the selectively monobenzy-
lated analogue. For instance, benzylated 13aneN4 16 is
The condensation of pyruvic aldehyde with tetraamine
1 in acetonitrile at 4 °C gives a mixture of two gem-cis
isomers, 3 and 4, in a 4:1 ratio (Scheme 1). The same
selectivity has been observed in the case of butane-
dione.31-33 No vic-isomer is observed because the forma-
tion of the adduct containing three six-membered rings
is strongly favored. The difference between the calculated
energies of the two most stable trans and cis isomers is
too slight (0.43 kcal.mol-1) to explain the absence of trans
isomer. The cis isomer is certainly kinetically favored via
(23) Cocolios, P.; Guilard, R.; Gros, C. Polyazacycloalkane deriva-
tives, their metal complexes and pharmaceutical products incorporat-
ing these complexes. WO 9611189, 1996.
(24) Guilard, R.; Meunier, I.; Jean, C.; Boisselier-Cocolios, B.
Preparation of 1,4,8,11-tetraazacyclotetradecanes and related macro-
cycles. EP 427595, 1991.
(25) Filali, A.; Yaouanc, J.-J.; Handel, H. Angew. Chem., Int. Ed.
Engl. 1991, 30, 560-561.
(26) Handel, H.; Yaouanc, J.-J.; Filali Zegzouti, A.; Malouala, D.;
Des Abbayes, H.; Clement, J. C.; Bernard, H.; Le Gall, G. Preparation
of mono-N-substituted cyclic tetramines. EP 389359, 1990.
(27) Bridger, G. J.; Skerlj, R. T.; Thornton, D.; Padmanabhan, S.;
Martellucci, S. A.; Henson, G. W.; Abrams, M. J.; Yamamoto, N.; De
Vreese, K.; Pauwels, R.; De Clercq, E. J. Med. Chem. 1995, 38, 366-
378.
(28) Le Baccon, M.; Chuburu, F.; Toupet, L.; Handel, H.; Soibinet,
M.; Dechamps-Olivier, I.; Barbier, J.-P.; Aplincourt, M. New J. Chem.
2001, 25, 1168-1174.
(29) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.;
Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K.
A.; Su, S.; Windus, S.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem.
1993, 14, 1347-1363.
(30) CS Chem3D 6.0, CambridgeSoft: Cambridge, MA, 2002.
(31) Herve´, G.; Bernard, H.; Le Bris, N.; Yaouanc, J.-J.; Handel, H.;
Toupet, L. Tetrahedron Lett. 1998, 39, 6861-6864.
(32) Stetter, H. Chem. Ber. 1953, 86, 69-74.
(33) Chuburu, F.; Tripier, R.; Le Baccon, M.; Handel, H. Eur. J. Org.
Chem. 2003, 68, 1050-1055.
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Regioselective N-Functionalization of Tetraazacycloalkanes
SCHEME 7 a
a Key: (i) BrCH2COOEt, K2CO3, CH3CN, reflux; (ii) H2, Pd/C, EtOH, rt.
TABLE 1. Selected Experimental and Calculated (in Italics) Bond Lengths (Å)
a Average distances.
the formation of iminium intermediates.33 The energy
comparison between the two gem-cis isomers, 3 and 4
(Scheme 1), indicates that the isomer 3 is more stable
than 4 by 4.44 kcal‚mol-1. This difference agrees well
with the experimental results. The most stable structure
was found to be the gem-cis compound 3 in which one of
the lone pairs, belonging to the secondary amine type
nitrogen atoms is lying in axial position while the other
one is in equatorial position. It is confirmed by the X-ray
structure of compound 3 (Figure 1a). This perfect agree-
ment between the experiment and the molecular model-
ing calculations shows the reliability of the theoretical
results (Figure 3). It has to be noted that the condensa-
tion of the tetraamine 1 with glyoxal leads to a mixture
of gem-cis and gem-trans compounds in slightly different
ratios depending on the experimental conditions.17,19,33-35
The preferential formation of the trans isomer reported
by Fuchs and co-workers36 is probably wrong since this
result is contrary to a previous report of the same group.34
The condensation of pyruvic aldehyde with N,N′-bis-
(3-aminopropyl)ethylenediamine 2 gives a mixture of vic-
trans isomer 5 and vic-cis isomer 6 in a 9:1 ratio (Scheme
J. Org. Chem, Vol. 70, No. 18, 2005 7047

Boschetti et al.
The reaction of the vic-trans isomer obtained from
the condensation of glyoxal and tetraamine 2 with 1,2-
dibromoethane in DMF in the presence of K2CO3 yielded
the protected cyclam in 65% yield (58% overall yield from
the linear tetraamine).20 The cyclization may also be
performed with glyoxal followed by reduction with so-
dium borohydride.37,38 It appears from all these results
that the main factor is the configuration of the bisaminal
intermediate. The results obtained with the different
R-dicarbonylated compounds could indicate that only the
vic-trans isomer is able to undergo cyclization from 2.
However, the cis configuration with pyruvic aldehyde
seems more suitable for the cyclization since the cycliza-
tion of the vic-cis isomer 6 occurs in 70% yield, while only
a small ratio (24%) of the vic-trans isomer 5 is cyclized.
Figure 5 represents the most stable structures obtained
from DFT/B3LYP/6.31 G* calculations for the bisaminal
adducts of tetraamine 2 with butanedione and pyruvic
aldehyde. In the cis intermediate obtained with butane-
dione, one of the two secondary amine type nitrogen
atoms is involved in a hydrogen bond with the hydro-
gen bound to the other secondary amine type nitrogen
(d(N4‚‚‚HN1) ) 2.186 Å, R ) 113.8°) and thus is not
available for nucleophilic substitution, while the lone pair
of this nitrogen is hindered by the methyl group on the
aminal carbon (Figure 5a). Moreover, the HN4 hydrogen
atom is also involved in a weak hydrogen bonding
interaction with N2 (d(N2‚‚‚HN4) ) 2.400 Å, R ) 117.9°).
Weaker interactions also exist in the glyoxal and pyruvic
aldehyde intermediates (d(N2‚‚‚HN4) ) 2.694 and 2.616
Å, respectively). Consequently, the cyclization for the
butanedione adduct is not possible. In the case of pyruvic
aldehyde, due to the presence of only one methyl group
on the bisaminal bridge, the nitrogen atom (N1) bound
to the aminal carbon bearing the methyl group is no more
hindered by the second methyl group and is able to attack
the biselectrophilic reagent (Figure 5b).
The elimination of the hydrogen resulting from this
nucleophilic substitution leaves the other secondary
amine nitrogen free from any hydrogen-bonding interac-
tion. Then the second nucleophilic substitution, i.e., the
cyclization reaction, can occur. Vic-trans isomer 5 un-
dergoes cyclization to a lesser extent than the analogous
glyoxal adduct due to the steric hindrance of the methyl
group on the rigid trans isomer. In the trans isomer, the
presence of methyl groups is prejudicial to the cyclization
reaction but does not completely forbid it, since com-
pounds 9 or even 30 have been obtained (Figure 4).
The various cis-bisaminal protected macrocycles show
different behaviors toward the quaternization reaction.
Indeed, the bisaminal compounds obtained from glyoxal
may undergo trans diquaternization, quaternization of
corresponding butanedione adducts being not possible,
while a selective monoquaternization occurs when pyru-
vic aldehyde is used as starting material. These different
behaviors are easily explained on the basis of X-ray
structures and molecular modeling. Indeed, protonation
of such cis-bisaminal protected macrocycles occurs on the
internal “concave” nitrogen atoms due to the convergence
of the lone pairs of these two nitrogen atoms and the
FIGURE 3. Chem3D overlay of the experimental RX and
DFT/B3LYP/6.31 G* calculated structures of 3 (hydrogen
atoms are omitted for clarity).
FIGURE 4. ORTEP view of 30 (hydrogen atoms are omitted
for clarity; ellipsoids are shown at 50% probability level).
1). The B3LYP/6.31 G* DFT calculations indicate that
the vic-cis isomer is slightly more stable than the vic-
trans by only 0.85 kcal‚mol-1. The formation of the major
vic-trans isomer is certainly due to kinetic parameters.
No trace of gem isomer is obtained because of the much
greater stability of the vic isomer which in this case is
the one containing three six-membered rings. The be-
havior of pyruvic aldehyde toward the tetraamine 2
appears to be closer to that of glyoxal than that of
butanedione. When glyoxal is used, the vic-trans com-
pound is mainly obtained (90%),17,20 while the vic-cis
isomer is formed predominantly (75%) by using butane-
dione.17,31,33
The cyclization reaction of the bisaminal adducts
depends strongly on the nature of the starting tetraamine
and R-dicarbonyl compound. The bisaminal-protected
macrocycles 7 and 8 are obtained in good overall yields
while the bisaminal adducts obtained from 2 and pyruvic
aldehyde cyclize with difficulty in the same conditions
(Scheme 2). It has been reported that cyclization of
bisaminal adducts 2:butanedione (mostly the vic-cis
isomer) with alkyl dibromides or ditosylates in the same
conditions was unsuccessful.31 However, the protected
macrocycle 30, in which the two methyl groups are in a
trans position, is isolated in 8% yield (Figure 4, Scheme
8). It indicates that the cyclization step of the trans
isomer occurs in 32% yield.
(34) Fuchs, B.; Ellencweig, A. Rec. Trav. Chim. Pays-Bas 1979, 98,
326-333.
(35) Perkins, C. M.; Kitko, D. J. MRI image enhancement composi-
tions containing tetraazabicyclohexadecane manganese complexes. WO
0226267, 2002.
(37) Okawara, T.; Takaishi, H.; Okamoto, Y.; Yamasaki, T.; Fu-
rukawa, M. Heterocycles 1995, 41, 1023-1033.
(38) Jazwinski, J.; Kolinski, R. A. Bull. Pol. Acad. Sci., Chem. 1989,
36, 215-220.
(36) Mueller, R.; Von Philipsborn, W.; Schleifer, L.; Aped, P.; Fuchs,
B. Tetrahedron 1991, 47, 1013-1036.
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Regioselective N-Functionalization of Tetraazacycloalkanes
SCHEME 8
small size of the proton.20 However, there is not enough
room for any entity larger than hydrogen and quater-
nization with methyl iodide for example takes place
partially hindered by the methyl group, as evidenced by
the X-ray structure of compounds 11 and 19 (Figure 1c,d)
and clearly shown in Figure 6. Thus, only selective
monoquaternization is possible. When two methyl groups
are present on the bisaminal bridge, in the case of
butanedione adduct, the two “convex” nitrogen atoms are
hindered. Therefore, none of the four nitrogen atoms is
available for quaternization.
Conclusion
The method reported in this work is a very powerful
route toward selectively functionalized tetraazacycloal-
kanes starting from linear tetraamines. This approach
presents two main advantages when compared to previ-
ous conventional methods. The first important feature,
which might be called the “organic template effect”, is
the rigidification of the linear tetraamine by the bisami-
nal bridge, favoring the cyclization reaction. This is a
main answer according to the two important concepts in
synthetic efficiency, i.e., atom economy and selectivity,
since significant amounts of macrocycles can be prepared
in good yields without using large volumes of solvents
or producing two much wastes, two drawbacks often
inherent to the synthesis of such cyclic compounds. The
second key point of the method is the use of the bisaminal
bridge as a protecting group before releasing the mono-
functionalized tetraazacycloalkane. Not only does the
same moiety play two crucial roles, but the bisaminal
bridge is easily introduced and removed under mild
conditions. The level of selectivity is higher than that of
most of known procedures for the preparation of func-
tionalized tetraazacycloalkanes, as evidenced by the
formation of only one out the two monofunctionalized
isomers in the 13aneN4 series. The scope of this method
has been extended to various electrophilic reagents.
Consequently this approach provides a very straightfor-
ward access to bismacrocycles.
FIGURE 5. DFT/B3LYP/6.31 G* calculated structures of the
vic-cis bis-aminal derived from 1,5,8,12-tetraazadodecane (323)
and (a) butanedione or (b) pyruvic aldehyde.
on the “convex” nitrogen atoms, pointing outside the
macrocyclic cavity. In the case of pyruvic aldehyde, only
one of the two “convex” nitrogen atoms is accessible for
quaternization. Indeed the “convex” nitrogen atom linked
to the aminal carbon bearing the hydrogen atom is
Experimental Section
Materials and Equipment. The 1H and 13C NMR spectra
were recorded on 300 or 500 MHz spectrometers at the “Centre
de Spectroscopie Mole´culaire de l′Universite´ de Bourgogne (FR
2604)”. The chemical shifts were measured by reference to the
residual protons or carbon signals of the deuterated solvent.
MALDI-TOF spectra were recorded using dithranol as a
matrix. LSIMS spectra were recorded using m-nitrobenzyl
alcohol as a matrix.
X-ray Diffraction Experiments and Data Processing.
High-quality colorless single-crystal specimens were selected
for the low-temperature X-ray diffraction experiments. The
X-ray source was graphite monochromatized Mo KR radiation
from a sealed tube. Measurements were collected39 on a
diffractometer, equipped with a nitrogen jet stream low-
FIGURE 6. DFT/B3LYP/6.31 G* calculated structure of 8.
J. Org. Chem, Vol. 70, No. 18, 2005 7049

Boschetti et al.
temperature system. For each crystal structure, the lattice
parameters were obtained by a least-squares fit to the opti-
mized setting angles of all collected reflections observed up to
the maximum diffraction angle 2θmax. Intensity data were
recorded as æ and ω scans with κ offsets. Data reduction was
done using the DENZO program.40 Table S1 (Supporting
Information) summarizes crystal data and some experimental
conditions.
determined by integration of the signals corresponding to the
methyl group in the 1H NMR spectrum. This mixture was used
for the next step without further purification. The minor
isomer has not been fully characterized by NMR because of
overlapped signals. Single crystals of 3 were obtained by slow
1
evaporation of pentane. H NMR of 3 (500 MHz, CDCl3, 220
K) δ, ppm: 1.22 (m, 1H); 1.30 (s, 3H); 1.70 (s, 2H); 2.17-2.28
(m, 4H); 2.61-2.67 (m, 2H); 2.89 (s, 1H); 2.90-3.00 (m, 4H);
3.09 (m, 2H); 3.18 (m, 1H). 13C NMR (125 MHz, CDCl3, 220
K) δ, ppm: (CH3-) 19.6; (CH2-â) 26.0; (CH2-R) 39.3; 40.8; 44.9;
53.4; 55.1; 56.6; (NCN) 65.3; 81.3. MALDI-TOF: m/z ) 196.28
Structure Solution and Refinement. The structures
were solved by direct methods using the SIR97 program.41
Refinements were carried out by full-matrix least squares on
F2 using the SHELXL97 program42 and the complete set of
reflections. In all cases, the applied weighting scheme was w
[M]+•
.
trans-4a-Methyldodecahydro-4,5,8a,10a-tetraaza-
phenanthrene 5 was prepared starting from N,N′-bis(3-
aminopropyl)ethylenediamine 2 (5.06 g; 28.73 mmol) and
pyruvic aldehyde (40 wt % solution in water; 5.16 g; 28.73
mmol). The crude product was a mixture of the two isomers 5
and 6 in a 9:1 ratio as determined by integration of the signals
) 1/[σ2(Fo ) + (aP)2 + bP] where P ) (Fo + 2 Fc2)/3, a and b
being updated parameters. Anisotropic thermal parameters
were used for non H-atoms. In all structures, the hydrogens
were located by Fourier synthesis and refined with a global
isotropic thermal factor. While in 9, 11, and 1915 hydrogens
were placed at calculated positions using a riding model, in
3,15 27, and 30 all H-atoms coordinates were refined. In 9, the
molecule was found to be disordered among two conformations
A/B, both occupying the same regions in the unit cell and
showing sites occupation factors of 0.5/0.5. The B conformer
can be described as the inverted image of A by an 1h-symmetry
element placed on the middle of the C14-C23 bond, in such a
way that all atomic sites (except those corresponding to the
methyl group and the hydrogen H23) are shared by pairs of
atoms corresponding to A and B conformers. Table S1 (Sup-
porting Information) summarizes structure refinement details
for the six compounds.
2
2
1
corresponding to the methyl group in the H NMR spectrum.
This mixture was used for the next step without further
purification. The minor isomer has not been fully characterized
1
by NMR because of overlapped signals. H NMR of isomer 5
(500 MHz, CDCl3, 300 K) δ, ppm: 1.05 (s, 3H); 1.33-1.40 (m,
2H); 1.50-1.60 (m, 2H); 1.96 (td; 1H, J ) 3.1 Hz, 12.4 Hz);
2.15-2.23 (m, 2H); 2.30 (s, 1H); 2.36-2.48 (m, 4H); 2.52 (td,
1H, J ) 3.4 Hz, 12.2 Hz); 2.67-2.69 (m, 2H); 2.74-2.78 (m,
2H); 2.91-2.95 (m, 2H). 13C NMR (125 MHz, CDCl3, 300 K) δ,
ppm: (CH3-) 8.11; (CH2-â) 27.1; 27.6; (CH2-R) 39.5; 45.7; 48.0;
49.6; 54.3; 56.0; (NCN) 70.6; 85.5. LSIMS: m/z ) 211.2 [M +
H]+.
Molecular Modeling. All molecular modeling calculations
were carried out using GAMESS (version 20 june 2002)29 on a
cluster at the “Centre des Ressources Informatiques de
l’Universite´ de Bourgogne”. The lowest energy conformers were
first located by low level calculations (semiempirical AM1
method). Then, for each derivative, all conformers having a
relative energy below 4 kcal‚mol-1 were calculated at the DFT/
B3LYP/6-31 G* level.
Chemicals. N,N′-Bis(2-aminoethyl)-1,3-propanediamine 1
was synthesized according to literature procedure.43 All other
chemicals were purchased from commercial suppliers and used
as received without further purification.
Typical Procedure for the Synthesis of Bisaminal
Adducts. To a solution of tetraamine in acetonitrile (ca. 0.15
M for the synthesis of intermediates 3 and 4, ca. 0.6 M for the
synthesis of intermediates isomer 5 and 6) cooled to 4 °C was
added dropwise 1 equiv of pyruvic aldehyde (40 wt % solu-
tion in water). After completion of the reaction (4 h), the
solution containing intermediates 3-6 was heated under
reflux, potassium carbonate (5 equiv) and 1 or 2 equiv of
dibromoethane or 1,3-dibromopropane were added for the
synthesis of 7 and 8 or 9 and 10, respectively. After 48 h, the
mixture was filtered over a pad of Celite, the filtrate was
evaporated, and the residue was chromatographed over an
alumina plug using dichloromethane as eluent to yield pure
compounds 7-10.
cis-9b-Methyldecahydro-2a,4a,7a,9a-tetraazacyclopen-
ta[cd]phenalene 7 was prepared starting from a crude
mixture of 3 and 4 (1.50 g; 7.65 mmol), potassium carbonate
(5.28 g; 38.25 mmol), and 1,2-dibromoethane (1.43 g; 7.65
mmol). Compound 7 was obtained as a colorless oil: yield 69%;
1
m ) 1.17 g; H NMR (500 MHz, CDCl3, 220 K) δ, ppm: 0.94
(s, 3H); 1.05 (m, 1H); 2.01 (m, 3H); 2.22-2.30 (m, 2H); 2.38-
2.51 (m, 4H), 2.66-2.85 (m, 6H); 3.02 (m, 2H); 3.20 (m, 1H).
13C NMR (125 MHz, CDCl3, 220 K) δ, ppm: (CH3-) 1.8;
(CH2-â) 20.0; (CH2-R) 45.6; 46.3; 46.7; 51.0; 51.8; 53.8; 54.5;
56.3; (NCN) 75.6; 81.8. LSIMS: m/z ) 223.2 [M + H]+. Anal.
Calcd for C12H22N4: C, 64.83; H, 9.97; N, 25.20. Found: C,
64.86; H, 9.52; N, 24.78.
cis-10b-Methyldecahydro-3a,5a,8a,10a-tetraazapy-
rene 8 was prepared starting from a crude mixture of 3 and
4 (12.24 g; 62.39 mmol), potassium carbonate (43.12 g; 311.97
mmol), and 1,3-dibromopropane (12.59 g; 62.39 mmol). Com-
pound 8 was obtained as a colorless oil: yield m ) 10.04 g;
1
68%; H NMR (500 MHz, CDCl3, 223 K) δ, ppm: 1.15-1.22
(m, 2H); 1.36 (s, 3H); 2.00-2.32 (m, 6H); 2.40-2.71 (m, 10H);
3.35 (m, 1H); 3.45 (m, 1H); 3.62 (m, 1H). 13C NMR (125 MHz,
CDCl3, 223 K) δ, ppm: (CH3-) 13.5; (CH2-â) 19.2; 19.4;
(CH2-R) 45.2; 45.2; 47.0; 49.2; 50.7; 53.3; 54.6; 56.9; (NCN) 70.8;
82.8. MALDI-TOF: m/z ) 236.7 [M]+•
.
trans-10b-Methyldecahydro-3a,5a,8a,10a-tetraazapy-
rene 9 was prepared starting from a crude mixture isomer of
5 and 6 (6.02 g; 28.73 mmol), potassium carbonate (19.86 g;
143.68 mmol), and 1,2-dibromoethane (10.78 g; 57.47 mmol).
After chromatography (Al2O3, eluent: CH2Cl2), a mixture of 9
and of the corresponding cis isomer 8 (ratio: 3:1 determined
by 1H NMR) was obtained. Compound 9 was isolated as a
white powder from the mixture after washing with cold
acetone, yield 22%; m ) 1.49 g. Single crystals of 9 were
cis-9a-Methyloctahydro-1,3a,6a,9-tetraazaphenalene 3
was prepared starting from N,N′-bis(2-aminoethyl)-1,3-pro-
panediamine 1 (1.22 g; 7.65 mmol) and pyruvic aldehyde (40
wt % solution in water; 1.38 g; 7.65 mmol). The crude product
was a mixture of the two isomers 3 and 4 in a 4:1 ratio as
(39) Nonius, B. V. Collect Program, Data Collection Sofware, Non-
ius: Delft, The Netherlands, 1998.
1
obtained by slow evaporation of acetone. H NMR (500 MHz,
(40) Otwinowski, Z.; Minor, W. In Methods Enzymol.; Carter, C. W.,
Sweet, P. R. M., Jr., Eds.; Academic Press: New York, 1997; Vol. 276,
p 307-326.
CDCl3, 300 K) δ, ppm: 1.08 (s, 3H); 1.34-1.48 (m, 2H); 1.75-
2.00 (m, 5H); 2.33-2.40 (m, 4H); 2.45-2.48 (m, 4H); 2.58-
2.63 (m, 4H); 2.80 (m, 2H).13C NMR (125 MHz, CDCl3, 300 K)
δ, ppm: (CH3-) 1.3; (CH2-â) 24.6; 25.2; (CH2-R) 47.6; 47.6; 48.8;
48.8; 54.5; 54.5; 54.8; 54.8; (NCN) 72.6; 89.6. MALDI-TOF: m/z
(41) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. J. Appl. Crystallogr. 1999, 32, 115-119.
(42) Sheldrick, G. M. SHELXL97: program for the refinement of
crystal structures; University of Gottingen: Germany, 1997.
(43) Pruckmayr, G. Imparting durable press properties to cellulosic
fabrics. US 3814580, 1974.
) 236.7 [M]+•
.
trans-11b-Methyldecahydro-3a,5a,8a,11a-tetraazacy-
clohepta[def]phenanthrene 10 was prepared starting from
7050 J. Org. Chem., Vol. 70, No. 18, 2005

Regioselective N-Functionalization of Tetraazacycloalkanes
a crude mixture of isomers 5 and 6 (6.02 g; 28.73 mmol),
potassium carbonate (19.86 g; 143.68 mmol), and 1,3-dibro-
mopropane (11.55 g; 57.47 mmol). Compound 10 was obtained
76.9; 88.2; (CH2dCH) 116.1; (CH-Ar) 127.2; (C-Ar) 127.4;
(CH-Ar) 132.9; (CH2dCH) 136.2; (C-Ar) 139.7. LSIMS: m/z )
339.2 [M - I]+. Anal. Calcd for C21H32N4I: C, 53.96; H, 6.90;
N, 11.99. Found: C, 53.74; H, 6.79; N, 11.96.
1
as a colorless oil, yield 25%; m ) 1.80 g. H NMR (500 MHz,
CDCl3, 300 K) δ, ppm: 1.31 (m, 1H); 1.33 (s, 3H); 1.68-1.71
(m, 2H); 1.74-1.95 (m, 3H); 2.01 (m, 1H); 2.29-2.33 (m, 2H);
2.53-2.69 (m, 9H); 2.85 (m, 1H); 2.98 (m, 1H); 3.13-3.19 (m,
2H); 3.34 (m, 1H). 13C NMR (125 MHz, CDCl3, 300 K) δ, ppm:
(CH3-) 7.6; (CH2-â) 23.8; 24.1; 26.3; (CH2-R) 48.0; 49.7; 50.2;
50.3; 51.2; 52.0; 54.6; 55.1; (NCN) 75.2; 86.8. MALDI-TOF: m/z
) 250.9 [M]+•. Anal. Calcd for C14H26N4: C, 67.16; H, 10.47;
N, 22.38. Found: C, 66.83; H, 10.81; N, 22.13.
Typical Procedure for the Quaternization of Bisami-
nal Adducts and Deprotection To Yield Monofunctiona-
lized Macrocycles. Stoichiometric amounts of bisaminal
adduct 7-9 and convenient electrophilic reagent were mixed
together in acetonitrile (ca. 0.5 M, a mixture of acetonitrile/
toluene 3:1 was used as a solvent for the synthesis of com-
pound 21, 1 equiv of NaI was added for the synthesis of
compounds 13, 21, and 23). The mixture was stirred at rt
for 24 h, the white precipitate formed was filtered off and
washed with diethyl ether, and the corresponding ammonium
salt (11-15, 19, 21-23) was obtained as a white powder. The
solid was dissolved in water (ca. 0.3 M), a 10-fold volume of 3
M aqueous NaOH solution was added, and the mixture was
refluxed for 12 h. The solution was extracted three times with
chloroform, and the combined organic phases were dried over
MgSO4 and evaporated to yield compounds 16-18, 20, 24, and
25.
cis-2a-Benzyl-9b-methyldecahydro-4a,7a,9a-triaza-2a-
azoniacyclopenta[cd]phenalene bromide 11 was prepared
starting from 7 (1.17 g; 5.27 mmol) and benzyl bromide (0.90
g; 5.27 mmol). Compound 11 was obtained as a white powder,
yield 53%, m ) 1.10 g. Single crystals of 11 were obtained by
slow evaporation of acetonitrile. 1H NMR (500 MHz, D2O, 300
K) δ, ppm: 1.38 (m, 1H); 1.63 (s, 3H); 2.14 (m, 1H); 2.5-2.8
(m, 3H); 2.9-3.1 (m, 8H); 3.38 (m, 3H); 3.6 (m, 1H); 3.88 (s,
1H); 4.16 (m, 1H); 4.6 (d, 1H, J ) 13.0 Hz); 4.86 (d, 1H, J )
13.0 Hz); 7.52-7.58 (m, 5H). 13C NMR (125 MHz, D2O, 300 K)
δ, ppm: (CH3-) 10.3; (CH2-â) 18.5; (CH2-R) 43.1; 44.7; 44.8;
47.0; 52.1; 53.2; 54.0; 58.7; (CH2-Ph) 59.5; (NCN) 77.3; 87.3;
(C-Ar) 127.9; (CH-Ar) 130.0; 131.2; 132.4. MALDI-TOF: m/z
) 312.7 [M - Br]+. Anal. Calcd for C19H29N4Br: C, 58.14; H,
7.46; N, 14.28. Found: C, 58.26; H, 7.87; N, 14.16.
cis-2a-Ethoxycarbonylmethyl-9b-methyldecahydro-
4a,7a,9a-triaza-2a-azoniacyclopenta[cd]phenalene io-
dide 14 was prepared starting from 7 (11.00 g; 49.50 mmol)
and iodoethyl acetate (10.59 g; 49.50 mmol). After the mixture
was stirred for 24 h at rt, 14 was precipitated by addition of
the mixture to 3 L of diethyl ether. Compound 14 was obtained
as an off-white powder, yield 48%, m ) 10.36 g. 1H NMR (300
MHz, D2O, 300 K) δ, ppm: 1.20 (t, 3H, J ) 7.2 Hz); 1.25 (m,
1H); 1.42 (s, 3H); 2.05 (m, 1H); 2.41 (m, 2H); 2.63-2.98 (m,
8H); 3.32 (m, 2H); 3.67 (s, 1H); 3.76-3.95 (m, 3H); 4.06-4.25
(m, 3H); 4.35 (d, 1H, J ) 16.6 Hz); 4.63 (d, 1H, J ) 16.6 Hz).
13C NMR (75 MHz, D2O, 300 K) δ, ppm: (CH3-) 10.6; 13.6;
(CH2-â) 18.4; (CH2-R) 42.9; 44.8; 45.2; 47.0; 51.9; 53.9; 54.8;
55.8; 60.9; (-CH2-O) 64.1; (NCN) 77.1; 88.6; (CdO) 165.1.
MALDI-TOF: m/z ) 309.2 [M - I]+.
cis-2a-(1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl)-9b-
methyldecahydro-4a,7a,9a-triaza-2a-azoniacyclopenta-
[cd]phenalene bromide 15 was prepared starting from 7
(2.00 g; 9.00 mmol), N-(bromomethyl)phthalimide (2.16 g; 9.00
mmol). Compound 15 was obtained as an off-white powder,
yield 42%, m ) 1.75 g. 1H NMR (500 MHz, D2O, 300 K) δ,
ppm: 1.46 (m, 1H); 1.76 (s, 3H); 2.16-2.26 (m, 1H); 2.56-
2.62 (m, 2H); 2.81 (m, 1H); 2.95 (m, 1H, J ) 4.0 Hz, 12.0 Hz);
3.00-3.14 (m, 5H); 3.31 (m, 1H, J ) 13.3 Hz); 3.41-3.52 (m,
3H); 3.61-3.67 (m, 1H); 3.84 (m, 1H, J ) 12.9 Hz); 3.93 (s,
1H); 4.29 (m, 1H, J ) 5.0 Hz, 12.0 Hz); 5.30 (d, 1H, J ) 13.1
Hz); 5.65 (d, 1H, J ) 13.1 Hz); 7.97-8.05 (m, 4H). 13C NMR
(125 MHz, D2O, 300 K) δ, ppm: (CH3-) 11.0; (CH2-â) 18.7;
(CH2-R) 43.2; 44.7; 44.9; 47.4; 52.3; 54.1; 54.4; 57.5;
(CH2-phthalimide) 59.9; (NCN) 77.9; 87.8; (CH-Ar) 125.2; (C-
Ar) 131.4; (CH-Ar) 136.6; (CdO) 169.8. MALDI-TOF: m/z )
382.4 [M - Br]+.
4-Benzyl-1,4,7,10-tetraazacyclotridecane 16 was pre-
pared starting from 11 (1.10 g; 2.80 mmol). Compound 16 was
obtained as a colorless oil, yield 80%, m ) 0.62 g. 1H NMR
(500 MHz, CDCl3, 300 K) δ, ppm: 1.70 (m, 2H); 2.20 (s, 3H);
2.58-2.66 (m, 10H); 2.75 (m, 4H); 2.8 (m, 2H); 3.62 (s, 2H);
7.26-7.30 (m, 5H). 13C NMR (125 MHz, CDCl3, 300 K) δ,
ppm: (CH2-â) 28.9; (CH2-R) 47.2; 47.9; 48.4; 48.4; 49.4; 50.7;
54.3; 54.4; (CH2-Ph) 60.4; (CH-Ar) 127.3; 128.5; 129.4; (C-Ar)
139.7. MALDI-TOF: m/z ) 276.7 [M]+•
.
cis-9b-Methyl-2a-(4-nitrobenzyl)decahydro-4a,7a,9a-
triaza-2a-azoniacyclopenta[cd]phenalene bromide 12
was prepared starting from 7 (1.94 g; 8.73 mmol) and p-
nitrobenzyl bromide (1.88 g; 8.73 mmol). Compound 12 was
4-(4-Nitrobenzyl)-1,4,7,10-tetraazacyclotridecane 17 was
prepared starting from 12 (1.00 g; 2.56 mmol). Compound 17
was obtained as a colorless oil, yield 64%, m ) 0.53 g. 1H NMR
(500 MHz, CDCl3, 300 K) δ, ppm: 1.61 (m, 2H); 2.49-2.91 (m,
19 H); 3.51 (s, 2H); 7.15 (m, 4H). 13C NMR (125 MHz, CDCl3,
300 K) δ, ppm: (CH2-â) 28.8; (CH2-R) 47.1; 47.9; 48.3; 48.4;
49.5; 50.7; 54.1; 54.2; (CH2-PhNO2) 60.0; (CH-Ar) 126.9; 129.3;
(C-Ar) 138.0; 141.6.
4-(4-Vinylbenzyl)-1,4,7,10-tetraazacyclotridecane 18 was
prepared starting from 13 (1.00 g; 2.14 mmol). Compound 18
was obtained as a colorless oil, yield 83%, m ) 0.54 g. 1H NMR
(500 MHz, CDCl3, 300 K) δ, ppm: 1.71 (m, 2H); 2.60-2.82 (m,
19H); 3.62 (s, 2H); 5.20 (dd, 1H, J ) 1.6 Hz, 10.8 Hz); 5.70
(dd, 1H, J ) 1.6 Hz, 17.6 Hz); 6.68 (dd, 1H, J ) 10.8 Hz, 17.6
Hz); 7.26 (d, 2H, J ) 5.7 Hz); 7.34 (d, 2H, J ) 5.7 Hz). 13C
NMR (125 MHz, CDCl3, 300 K) δ, ppm: (CH2-â) 29.0; (CH2-R)
47.3; 48.0; 48.5; 48.5; 49.5; 50.8; 54.3; 54.5; (CH2-Ph)
60.2; (CH2dCH) 113.7; (CH-Ar) 126.5; 129.6; (C-Ar) 136.8;
(CH2dCH) 137.1; (C-Ar) 139.4. MALDI-TOF: m/z ) 303.1 [M
+ H]+.
1
obtained as a white powder, yield 55%, m ) 2.10 g. H NMR
(500 MHz, D2O, 300 K): 1.37 (m, 1H); 1.64 (s, 3H); 2.12 (m,
1H); 2.50 (m, 2H); 2.55 (m, 1H); 2.86-3.09 (m, 8H); 3.39 (m,
2H); 3.50 (m, 1H); 3.70 (m, 1H); 3.88 (s, 1H); 4.21 (m, 1H);
4.72 (d, 1H, J ) 13.3 Hz); 5.01 (d, 1H, J ) 13.3 Hz); 7.77 (d,
2H, J ) 8.5 Hz); 8.27 (d, 2H, J ) 8.5 Hz). 13C NMR (125 MHz,
D2O, 300 K) δ, ppm: (CH3-) 10.3; (CH2-â) 18.5; (CH2-R) 43.1;
44.7; 44.9; 46.9; 52.1; 53.8; 54.0; 57.5; (CH2-PhNO2) 59.7;
(NCN) 77.3; 88.0; (CH-Ar) 124.9; 133.7; (C-Ar) 135.1; 149.3.
MALDI-TOF: m/z ) 358.2 [M - Br]+.
cis-9b-Methyl-2a-(4-vinylbenzyl)decahydro-4a,7a,9a-
triaza-2a-azoniacyclopenta[cd]phenalene iodide 13 was
prepared starting from 7 (1.00 g; 4.50 mmol), 4-vinylbenzyl
chloride (0.68 g; 4.50 mmol), and sodium iodide (0.67 g; 4.50
mmol). Compound 13 was obtained as a white powder, yield
61%, m ) 1.28 g. 1H NMR (500 MHz, D2O, 300 K) δ, ppm:
1.33 (m, 1H); 1.56 (s, 3H); 2.08 (m, 1H); 2.45 (m, 2H); 2.65 (m,
1H); 2.82-2.98 (m, 7H); 3.08 (m, 1H); 3.25-3.40 (m, 3H); 3.58
(m, 1H); 3.78 (s, 1H); 4.06 (m, 1H); 4.54 (d, 1H, J ) 13.2 Hz);
4.76 (d, 1H, J ) 13.2 Hz); 5.33 (d, 1H, J ) 11.0 Hz); 5.85 (d,
1H, J ) 17.7 Hz); 6.74 (dd,1H, J ) 11.0 Hz, 17.7 Hz); 7.42 (d,
2H, J ) 8.2 Hz); 7.53 (d, 2H, J ) 8.2 Hz). 13C NMR (125 MHz,
D2O, 300 K) δ, ppm: (CH3-) 12.1; (CH2-â) 19.6; (CH2-R) 43.7;
45.5; 45.7; 47.3; 52.8; 54.4; 54.7; 58.0; (CH2-Ph) 60.0; (NCN)
cis-3a-Benzyl-10b-methyldecahydro-5a,8a,10a-triaza-
3a-azoniapyrene bromide 19 was prepared starting from 8
(3.00 g; 12.70 mmol) and benzyl bromide (2.17 g; 12.70 mmol).
Compound 19 was obtained as a white powder, yield 51%, m
) 2.63 g. Single crystals of 19 were obtained by slow evapora-
1
tion of chloroform. H NMR (500 MHz, D2O, 300 K) δ, ppm:
1.33 (m, 1H); 1.67 (m, 1H); 1.74 (s, 3H); 2.00-2.20 (m, 2H);
J. Org. Chem, Vol. 70, No. 18, 2005 7051

Boschetti et al.
2.36 (dd, 1H, J ) 11.5 Hz, 4.0 Hz); 2.56 (td, 1H, J ) 12.5 Hz,
3.5 Hz); 2.65-3.01 (m, 9H); 3.16 (dd, 1H, J ) 13.0 Hz, 4.5 Hz);
3.20 (td, 1H, J ) 14.0 Hz, 2.5 Hz); 3.51 (td, 1H, J ) 12.0 Hz,
5.0 Hz); 3.82 (td, 1H, J ) 13.5 Hz, 4.5 Hz); 3.95 (s, 1H); 4.33
(td, 1H, J ) 12.5 Hz); 4.33 (d, 1H, J ) 13.0 Hz); 5.09 (d, 1H,
J ) 13.0 Hz); 7.50 (m, 5H). 13C NMR (125 MHz, D2O, 300 K)
δ, ppm: (CH3-) 9.9; (CH2-â) 17.7; 18.7; (CH2-R) 42.2; 46.2; 47.0;
47.4; 50.4; 52.3; 54.8; 56.2; (CH2-Ph) 58.9; (NCN) 76.9;
86.0; (C-Ar) 126.3; (CH-Ar) 129.6; 131.2; 133.7. MALDI-TOF:
m/z ) 327.2 [M - Br]+. Anal. Calcd for C20H31N4Br, CHCl3:
C, 48.08; H, 6.15; N, 10.69. Found: C, 48.74; H, 6.78; N,
10.94.
1-Benzyl-1,4,8,11-tetraazacyclotetradecane 20 was pre-
pared starting from 19 (2.70 g; 6.65 mmol). Compound 20 was
obtained as a colorless oil, yield 82%, m ) 1.58 g. NMR data
for 20 were consistent with those reported in the literature.12
trans-3a-Benzyl-10b-methyldecahydro-5a,8a,10a-triaza-
3a-azoniapyrene iodide 21 was prepared starting from 9
(0.30 g; 1.27 mmol), benzyl bromide (0.22 g; 1.27 mmol), and
sodium iodide (0.18 g; 1.27 mmol). Compound 21 was obtained
as a white powder, yield 52%, m ) 0.30 g. 1H NMR (500 MHz,
D2O, 300 K) δ, ppm: 1.70-1.85 (m, 3H); 1.94 (s, 3H); 2.28 (m,
1H); 2.51-2.54 (m, 2H); 2.60-2.75 (m, 2H); 2.80-2.89 (m, 2H);
2.93-3.05 (m, 4H); 3.11-3.15 (m, 2H); 3.34-3.49 (m, 5H); 5.19
(d, 1H, J ) 13.9 Hz); 5.53 (d, 1H, J ) 13.9 Hz); 7.56-7.65
(m, 5H). 13C NMR (125 MHz, D2O, 300 K) δ, ppm: (CH3-) 8.9;
(CH2-â) 18.5; 23.4; (CH2-R) 45.4; 47.4; 49.2; 51.4; 51.7; 52.0;
52.7; 53.4; (CH2-Ph) 54.2; (NCN) 79.8; 86.5; (C-Ar) 128.2; 130.1;
131.4; 133.3.
0.10 mol) and potassium carbonate (8.00 g; 58.00 mmol) in
450 mL of chloroform was added dropwise a solution of
ethylbromoacetate (3.34 g; 20.00 mmol) in 50 mL of chloro-
form. After being stirred at rt for 48 h, the mixture was fil-
tered over a pad of Celite, the filtrate was evaporated un-
der reduced pressure, and the residue was taken into petro-
leum ether. After filtration of the excess of cyclam, the fil-
trate was evaporated to give 26 as a slightly yellow oil, yield
97%. 1H NMR (500 MHz, CDCl3, 300 K) δ, ppm: 1.20 (t,
3H, J ) 7.0 Hz); 1.65-1.71 (m, 4H); 2.56-2.71 (m, 19H);
3.31 (s, 2H); 4.07 (q, 2H, J ) 7.0 Hz). 13C NMR (125 MHz,
CDCl3, 300 K) δ, ppm: (CH3-) 14.7; (CH2-â) 26.7; 29.4;
(CH2-R) 47.8; 48.3; 49.2; 49.4; 49.7; 51.2; 52.8; 53.6; 55.9;
(CH2-O) 60.5; (CdO) 171.5. MALDI-TOF: m/z ) 286.9 [M]+•
,
309.2 [M + 23]+.
Synthesis of 1,5,8,12-Tetraazabicyclo[10.2.2]hexadecan-
13-one 27. Compound 26 slowly undergoes intramolecular
cyclization to give 27. The conversion was almost complete
after 10 days at room temperature, total after refluxing 48 h
in acetonitrile. 1H NMR (500 MHz, CDCl3, 300 K) δ, ppm:
1.60-1.75 (m, 2H); 1.90-2.00 (m, 1H); 2.02-2.13 (m, 1H);
2.26-2.34 (td, 1H, J ) 12.3 Hz, 4.9 Hz)); 2.47-2.86 (m, 10H);
2.91 (d, 1H, J ) 15.5 Hz); 2.98 (dd, 1H, J ) 12.0 Hz, 7.0 Hz);
3.05 (dd, 1H, J ) 11.0 Hz, 5.5 Hz); 3.11 (dd, 1H, J ) 11.5 Hz,
4.5 Hz); 3.29 (m, 1H); 3.37 (dd, 1H, J ) 15.5 Hz, 3.4 Hz); 3.90
(td, 2H, J ) 11.9 Hz, 6.5 Hz); 4.33 (m, 1H). 13C NMR (125
MHz, CDCl3, 300 K) δ, ppm: (CH2-â) 24.6; 26.8; (CH2-R) 47.7;
48.1; 48.5; 48.8; 49.9; 50.2; 51.0; 56.4; 59.0 (C ) O) 167.9.
MALDI-TOF: m/z ) 240.7 [M]+•
.
cis-9b-Methyl-2a-[4-(9b-methyldecahydro-2a,4a,7a,9a-
tetraazacyclopenta[cd]phenalen-2a-ylmethyl)benzyl]-
decahydro-4a,7a,9a-triaza-2a-azoniacyclopenta[cd]phe-
nalene dibromide 22 was prepared starting from 7 (1.00 g;
4.50 mmol) and R,R′-dibromo-p-xylene (0.59 g; 2.25 mmol).
Compound 22 was obtained as a white powder, yield 59%, m
) 0.94 g. 1H NMR (300 MHz, D2O, 300 K): 1.05 (m, 2H); 1.32
(s, 6H); 2.03 (m, 2H); 2.40-2.70 (m, 6H); 2.75-3.15 (m, 16H);
3.20-3.65 (m, 8H); 3.80 (s, 2H); 4.08 (m, 2H); 4.60 (d, 2H, J )
13.3 Hz); 4.86 (d, 2H, J ) 13.3 Hz); 7.59 (s, 4H). 13C NMR (75
MHz, D2O, 300 K) δ, ppm: (CH3-) 10.2; (CH2-â) 18.4; (CH2-R)
43.0; 44.6; 44.7; 46.8; 51.9; 53.4; 53.9; 57.8; (CH2-Ph) 59.4;
(NCN) 77.2; 87.5; (C-Ar) 130.5; (CH-Ar) 133.3. MALDI-TOF:
m/z ) 551.6 [M - 2Br]+.
Synthesis of (4-Benzyl-7,10-diethoxycarbonylmethyl-
1,4,7,10-tetraazacyclotridec-1-yl)acetic Acid Ethyl Ester
28. To a suspension of 16 (1.62 g; 5.87 mmol) and potassium
carbonate (4.87 g; 35.22 mmol) in 100 mL of acetonitrile was
added ethyl bromoacetate (2.94 g; 17.61 mmol). The mixture
was refluxed for 2 days and then filtered, and the solvent was
removed under reduced pressure. The residual oil was taken
up in pentane. After filtration, solvents were evaporated to
1
give 28 as a pale yellow oil, yield 72%, m ) 2.25 g. H NMR
(500 MHz, CDCl3, 300 K) δ, ppm: 1.21-1.29 (m, 9H); 1.60 (m,
2H); 2.60 (m, 4H); 2.75 (m, 8H); 2.86 (m, 4H); 3.20 (s, 2H);
3.35 (s, 2H); 3.38 (s, 2H); 3.53 (s, 2H); 4.10-4.17 (m, 6H);
7.20-7.36 (m, 5H). 13C NMR (125 MHz, CDCl3, 300 K) δ,
ppm: (CH3-) 14.9 (×3); (CH2-â) 25.3; (CH2-R) 51.2; 51.6; 52.1;
52.2; 52.6; 52.6; 52.9; 53.2; 55.5; 56.1; 56.4; (CH2-Ph) 60.2;
(CH2-O) 60.6; 60.7; 60.8; (CH-Ar) 127.3; 128.7; 129.6; (C-Ar)
140.4; (CdO) 172.2; 172.3; 172.4. MALDI-TOF: m/z ) 534.9
cis-10b-Methyl-3a-[4-(10b-methyldecahydro-3a,5a,8a,-
10a-tetraazapyren-3a-ylmethyl)benzyl]decahydro-5a,-
8a,10a-triaza-3a-azoniapyrene dibromide 23 was prepared
starting from 8 (1.65 g; 6.98 mmol), R,R′-dibromo-p-xylene (0.92
g; 3.49 mmol), and sodium iodide (1.04 g; 6.98 mmol). Com-
pound 23 was obtained as a white powder, yield m ) 1.54 g,
[M]+•
.
Synthesis of (7,10-Diethoxycarbonylmethyl-1,4,7,10-
tetraazacyclotridec-1-yl)acetic Acid Ethyl Ester 29. To
a solution of 28 (2.20 g; 4.12 mmol) in 250 mL of ethanol was
added Pd/C (300 mg). The mixture was stirred at room
temperature under hydrogen atmosphere for 12 h. After
filtration over a pad of Celite and evaporation of the solvent
under reduced pressure, 29 was obtained quantitatively as a
1
53%. H NMR (500 MHz, D2O, 300 K) δ, ppm: 1.40 (m, 2H);
1.79 (m, 2H); 1.83 (s, 6H); 2.10-2.29 (m, 4H); 2.45 (m; 2H);
2.70-3.08 (m, 20H); 3.33 (m, 4H); 3.56 (m, 2H); 3.95 (m, 2H);
4.12 (s, 2H); 4.42-4.50 (m, 4H); 5.28 (d, 2H, J ) 13.2 Hz);
7.72 (s, 4H). 13C NMR (125 MHz, D2O, 300 K) δ, ppm: (CH3-)
10.2; (CH2-â) 18.0; 19.0; (CH2-R) 42.4; 46.4; 47.6; 47.6; 50.7;
52.5; 55.0; 56.7; (CH2-Ph) 58.5; (NCN) 76.9; 86.6; (C-Ar) 129.3;
(CH-Ar) 134.8. MALDI-TOF: m/z ) 576.5 [M - 2I]+.
1
colorless oil. H NMR (500 MHz, CDCl3, 300 K) δ, ppm: 1.15
(m, 9H); 1.60 (m, 2H); 2.60 (m, 9H); 2.71 (m, 2H); 2.97 (m,
2H); 3.02 (m, 4H); 3.22 (s, 2H); 3.38 (s, 2H); 3.39 (s, 2H); 4.04
(m, 6H). 13C NMR (125 MHz, CDCl3, 300 K) δ, ppm: (CH3-)
14.6 (×3); (CH2-â) 23.8; (CH2-R) 45.0; 46.3; 49.6; 50.9; 51.3;
51.5; 53.0; 54.0; 54.5; 56.6; 58.2; (CH2-O) 60.8; 60.9; 61.0;
(CdO) 171.3; 171.5; 171.5. MALDI-TOF: m/z ) 445.3 [M +
4,4′-[1,4-Phenylenebis(methylene)]bis-1,4,7,10-tetraaza-
cyclotridecane 24 was prepared starting from 22 (0.50 g; 0.71
mmol). Compound 24 was obtained as a colorless oil, yield 41%,
m ) 0.14 g.1H NMR (500 MHz, CDCl3, 300 K) δ, ppm: 1.40
(m, 4H); 2.30-2.90 (m, 38H); 3.48 (s, 4H); 7.17 (s, 4H). 13C
NMR (125 MHz, CDCl3, 300 K) δ, ppm: (CH2-â) 28.8; (CH2-R)
46.9; 47.8; 48.2; 48.3; 49.5; 50.7; 54.1; 54.1; (CH2-Ph) 60.0; (CH-
H]+•
.
Synthesis of trans-10b,10c-Dimethyldecahydro-3a,5a,-
8a,10a-tetraazapyrene 30. To a solution of N,N′-bis(3-
aminopropyl)ethylenediamine 2 (2.78 g; 15.94 mmol) in 100
mL of acetonitrile cooled to 4 °C was added dropwise 1 equiv
of butanedione (1.37 g; 15.94 mmol). After completion of the
reaction (4 h), the solution was heated under reflux, and
potassium carbonate (11.01 g; 79.70 mmol) and 2 equiv of
dibromoethane (5.98 g; 31.87 mmol) were added. After 48 h,
the mixture was filtered over a pad of Celite, the filtrate was
evaporated, and the residue was chromatographed over an
Ar) 129.4; (C-Ar) 138.5. MALDI-TOF: m/z ) 476 [M + H]+•
.
1,1′-[1,4-Phenylenebis(methylene)]bis-1,4,8,11-tetraaza-
cyclotetradecane 25 was prepared starting from 23 (1.00 g;
1.20 mmol). Compound 25 was obtained as colorless oil, yield
70%, m ) 0.46 g. NMR data for 25 were consistent with those
reported in the literature.10
Synthesis of (1,4,8,11-Tetraazacyclotetradec-1-yl)ace-
tic acid ethyl ester 26. To a mixture of cyclam (20.0 g;
7052 J. Org. Chem., Vol. 70, No. 18, 2005

Regioselective N-Functionalization of Tetraazacycloalkanes
1
alumina plug using dichloromethane as eluent to yield pure
30 as a white powder, yield 8%, m ) 0.30 g. 1H NMR (500
MHz, CDCl3, 300 K) δ, ppm: 1.32 (s, 6H); 1.58 (m, 2H); 1.95-
2.03 (m, 2H); 2.41-2.59 (m, 12H); 2.81 (m, 4H). 13C NMR
(125 MHz, CDCl3, 300 K) δ, ppm: (CH3-) -0.2; (CH2-â) 25.7;
(CH2-R) 48.5; 49.1; (NCN) 76.3. MALDI-TOF: m/z ) 250.8
tures. H and 13C spectra of 3, 7-16, 18, 19, 21, 22, 24, and
26-30. This material is available free of charge via the
Internet at http://pubs.acs.org. Crystallographic data corre-
sponding to the structural analysis of 9, 11, 27, and 30 have
been deposited with the Cambridge Crystallographic Data
Centre, CCDC Nos. 216209-216212. Copies of this information
may be obtained from the Director, CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (fax: +44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk).
[M]+•
.
Supporting Information Available: Crystal and struc-
ture refinement data for 3, 9, 11, 19, 27, and 30 (Table S1).
Computer modeling energies for the various studied struc-
JO050306U
J. Org. Chem, Vol. 70, No. 18, 2005 7053