Direct preparation of unsymmetrical difunctionalized cyclen derivatives by an ugi multicomponent reaction

Article abstract of DOI:10.1021/ol802674r

(Chemical Equation Presented) A new and efficient synthetic protocol for the preparation of unsymmetrical difunctionalized cyclen and its close derivatives using a modified Ugi reaction (N-split Ugi) is described. The scope of this methodology is further

Full text of DOI:10.1021/ol802674r

ORGANIC
LETTERS
2009
Vol. 11, No. 2
417-420
Direct Preparation of Unsymmetrical
Difunctionalized Cyclen Derivatives by
an Ugi Multicomponent Reaction
Giovanni Piersanti,*,† Francesco Remi,† Vieri Fusi,‡ Mauro Formica,‡
Luca Giorgi,‡ and Giovanni Zappia*,†
Institute of Medicinal Chemistry, and Institute of Chemical Sciences, UniVersity of
Urbino “Carlo Bo”, Piazza del Rinascimento 6, 61029 Urbino (PU), Italy
gioVanni.piersanti@uniurb.it; gioVanni.zappia@uniurb.it
Received November 19, 2008
ABSTRACT
A new and efficient synthetic protocol for the preparation of unsymmetrical difunctionalized cyclen and its close derivatives using a modified
Ugi reaction (N-split Ugi) is described. The scope of this methodology is further extended by the successful use of various isocyanides, highly
functionalized carboxylic acids, and aldehydes.
Functionalized tetraazacycloalkanes have been widely stud-
ied, due to their ability to chelate a wide variety of metal
cations.1 Particularly, the N-functionalization of 12-mem-
bered saturated tetraazamacrocycles, such as 1,4,7,10-tet-
raazacyclododecane (cyclen), has been the subject of intense
investigation, mainly due to their extensive use as MRI
contrast agents,2 radiodiagnostic and radiotherapeutic agents,3
and fluorescent and luminescent sensors (Figure 1).4 In
addition, some cyclen metal complexes have been used in
molecular recognition and catalysis5 and as anti-HIV and
Figure 1. Structure of cyclen and some of its derivatives that have
received special attention.
† Institute of Medicinal Chemistry.
‡ Institute of Chemical Sciences.
anticancer agents.6 All of these applications require fine-
tuning of the chelating properties of the ligand derivative
by changing the nature, the number, and the relative position
of the functional groups. Moreover, many applications
demand the synthesis of macrocycles bearing two distinct
functional groups: one for coordination of the metal, and
(1) (a) Meyer, M.; Dahaoui-Gindrey, V.; Lecomte, C.; Guilard, R. Coord.
Chem. ReV. 1998, 180, 1313–1405. (b) Wainwright, K. P. Coord. Chem.
ReV. 1997, 166, 35–90. (c) Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.;
Bruening, R. L. Chem. ReV. 1995, 95, 2529–2586.
(2) (a) Caravan, P. Chem. Soc. ReV. 2006, 35, 512–523. (b) Aime, S.;
Crich, S. G.; Gianolio, E.; Giovenzana, G. B.; Tei, L.; Terreno, E. Coord.
Chem. ReV. 2006, 250, 1562–1579.
(3) Liang, X.; Sadler, P. J. Chem. Soc. ReV. 2004, 33, 246–266.
(4) Bunzli, J.-C. G.; Piguet, C. Chem. Soc. ReV. 2005, 34, 1048–1077.
(5) Reichenbach-Klinke, R.; Ko¨nig, B. J. Chem. Soc., Dalton Trans.
2002, 121–130.
(6) Wan, S.; Liang, F.; Xiong, X.; Yang, L.; Wu, X.; Wang, P.; Zhou,
X.; Wu, C. Bioorg. Med. Chem. Lett. 2006, 16, 2804–2806.
10.1021/ol802674r CCC: $40.75
Published on Web 12/17/2008
2009 American Chemical Society

another for anchoring onto a solid support (silica gel, organic
polymers) or a macromolecule (antibody, protein).7 The
synthesis of such bifunctional chelating agents (BCAs) has
attracted increasing interest, but selective difunctionalization
of cyclen is still difficult to achieve. Only a few methods
have been reported,8 although there is often poor selectivity
in the formation of the mono-over the di-N-functionalized
derivative. In general, N-derivatization has been accom-
plished by either direct derivatization or by a protection-
derivatization-deprotection sequence of reactions.8b Litera-
ture reports on mono-, bis-, and triderivatization by either
approach are known. However, bis-derivatization procedures
are scarce and are of particular interest given the possibility
of obtaining either symmetrical or unsymmetrical N1,N4 and/
or N1,N7 polyazamacrocyclic derivatives. For all of these
reasons, new and versatile methods, which simplify the
preparation of regioselective unsymmetrical BCAs, are highly
desiderable.
nent variation recently described by Tron et al.13 Thus, this
application of novel Ugi 4CR gives access to a variety of
unsymmetrical bis-functionalized cyclen derivatives, and the
strategy can be varied to incorporate different substituents
by simply changing the acid, carbonyl, and/or isocyanide
component. In addition, a mechanism is proposed based on
experiments using linear symmetrical secondary diamines.
Treatment of cyclen 1 with equimolar amounts of paraform-
aldehyde, acetic acid, and cyclohexylisocyanide in methanol
(1 M) at room temperature for 16 h provided the macrocycles
N1,N4 disubstituted 2a and N1,N7 disubstituted 2b in a 1:1
ratio (57% yield, Scheme 1).14 However, when the reaction
Scheme 1. Possibile Pathways for the Formation of 2a and 2b
Multicomponent reactions (MCRs) are one of the best tools
in modern organic synthesis to generate compound libraries
for screening purposes because of their productivity, simple
procedures, convergence, and facile execution.9 Therefore,
the design of novel MCRs has attracted great attention from
research groups working in diverse areas such as drug
discovery, supramolecular chemistry, and material science.
In particular, MCRs that involve isocyanides are by far the
most versatile reactions in terms of scaffolds and number of
accessible compounds, and they form the basis of the well-
known Passerini10 and Ugi reactions.11 The Ugi four-
component reaction (Ugi 4CR) is one of the cornerstones in
this field, and great efforts have been devoted to the
exploration of the potential of this transformation.12 The Ugi
4CR is a highly efficient process in which usually a primary
amine, a carbonyl compound, a carboxylic acid, and an
isocyanide react in one pot to give R-acylamino amides
(peptoids). The incorporation of hostlike macrocycles into
an Ugi-peptoid backbone represents a completely new and
promising outlook for molecular recognition studies.12e
In the present paper, we report the first direct synthesis of
unsymmetrical bis-functionalized cyclen and some of its
analogues using an N-split-Ugi 4CR, a clever multicompo-
was performed under reflux conditions, the ratio of 2a/2b
obtained was a 1:2 ratio in comparable yield. This occurred
even though, statistically, 2a is twice as likely to form as
2b as the major product. Two experiments have been
performed to gain more insight into the reaction. When a
1:1 mixture of 2a/2b was heated to reflux in methanol for
96 h, the ratio changed to 1:2 in favor of 2b; the same result
was obtained when pure 2a or 2b compounds were used.
Clearly, an equilibrium takes place between the N1,N4-
and N1, N7-substituted compounds, with transfer of the acetyl
group from one nitrogen to the other.
(7) Mishra, A. K.; Panwar, P.; Hosono, M.; Chuttani, K.; Mishra, P.;
Sharma, R. K.; Chatal, J. J. Drug Target 2004, 12, 559–567.
(8) For recent reviews: (a) Suchy´, M.; Hudson, R. H. E. Eur. J. Org.
Chem. 2008, 29, 4847–4865. (b) Denat, F.; Brande`s, S.; Guilard, R. Synlett
2000, 56, 1–574For selected examples: (c) Yoo, J.; Reichert, D. E.; Welch,
M. J. Chem. Commun. 2003, 766–767. (d) Manning, H. C.; Bai, M.;
Anderson, B. M.; Lisiak, R.; Samuelson, L. E.; Bornhop, D. J. Tetrahedron
Lett. 2005, 46, 4707–4710. (e) Zhang, S.; Jiang, X.; Sherry, A. D. HelV.
Chim. Acta 2005, 88, 923–935. (f) De Leo`n-Rodr`ıguez, L. M.; Kovacs, Z.;
Esqueda-Oliva, A. C.; Miranda-Olveraa, A. D. Tetrahedron Lett. 2006, 47,
6937–6940.
(9) For a monograph see: Zhu, J.; Bienayme, H. Multicomponent
Reactions; Wiley-VCH: Weinheim, Germany, 2005.
(10) Passerini, M. Gazz. Chim. Ital. 1922, 52, 126–129. Passerini, M.
Gazz. Chim. Ital. 1922, 52, 181–189.
(13) Giovenzana, G. B.; Tron, G. C.; Di Paola, S.; Menegotto, I. G.;
Pirali, T. Angew. Chem., Int. Ed. 2006, 45, 1099–1102.
(11) Ugi, I.; Meyr, R. Angew. Chem. 1958, 70, 702–703.
(12) (a) Do¨mling, A. Chem. ReV. 2006, 106, 17–89. (b) Marcaccini, S.;
Torroba, T. Nat. Protoc. 2007, 2, 632–639. (c) Do¨mling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3168–3210. (d) Ugi, I.; Werner, B.; Do¨mling, A.
Molecules 2003, 8, 53–56. During the preparation of the present manuscript,
a cyclen-derived carboxylic acid was used in Ugi multicomponent reaction:
(e) Main, M.; Snaith, J. S.; Meloni, M. M.; Jauregui, M.; Sykes, D.;
Faulkner, S.; Kenwright, A. M. Chem. Commun. 2008, 5212–5214.
(14) Compounds 2a and 2b were separated, with difficulty, by normal
phase chromatography using acetonitrile/ammonia as an eluent. Although
the 1H NMR spectra of these compounds are quite complicated due to
hindered rotations around the amide bonds, they were judged pure by
elemental analysis and 13C NMR. The different symmetry between 2a (less
symmetrical) and 2b (more symmetrical) allowed the correct assignment
by comparison of the two 13C NMR.
418
Org. Lett., Vol. 11, No. 2, 2009

After screening numerous solvents, methanol was found
to be the best. This solvent has ideal polarity for reagents
solubility, therefore providing the highest yields and simplest
workup of the reaction. No reaction took place when water
was employed.15
Scheme 2
.
Compounds Obtained by Variation of the
Bis-Secondary Aminea
The methodology was then extended to other 12-
membered polyazamacrocycles such as 1,7-dimethylcyclen
3,16 1,7-dioxacyclen 4,17 and 1,7-di-Cbz-cyclen 5.18 The
choice was inspired by the relevance of these scaffolds used
in molecular recognition and by their easy availability. All
of these compounds contain the same substructure, namely,
1,7-bis secondary diamine separated by an aliphatic chain
containing a heteroatom. As well as cyclen, 3, 4, and 5 were
successfully subjected to the N-split-Ugi 4CR protocol using
paraformaldehyde, cyclohexyl isocyanide, and acetic acid
(Scheme 2). As shown, although the desired conversion
always occurred, longer times were needed for 4 and 5 to
give comparable yields. In addition, to further test the
approach and to get more insight into the mechanism, two
linear symmetrical secondary diamines 6 and 7 were used.19
While compund 6 reacted similarly to cyclen 2 and dimeth-
ylcyclen 3, pyridine derivative 7 furnished the corresponding
product in less time at room temperature.
From these experiments, we can observe that the confor-
mational flexibility of the linking moiety connecting the two
secondary amines as well as the nature and the electronic
properties of the internal heteroatoms evidently play a crucial
role. However, precise rationalization cannot be given at this
point.
a A: paraformaldehyde (1 equiv), cyclohexylisocyanide (1 equiv), acetic
acid (1 equiv) in methanol (1 M). Yield of the isolated product.
The generality for the functionalization of dimethylcyclen
3 was then validated by varying the single components.6,16
Besides formaldehyde (Table 1, entry 1), butyraldehyde
(Table 1, entry 2) and benzaldehyde (Table 1, entry 3) were
successfully employed as the carbonyl compound. Ugi
product formation was negligible or not observed when
cyclopentanone (Table 1, entry 4) was employed, whereas
the Passerini 3-CR (P-3CM) product 16 was isolated (see
Supporting Information). Steric hindrance could be envisaged
to explain the lack of the desired reaction, although the
classical Ugi 4CR has been reported to be quite insensitive
to steric hindrance.12c Notably, a lower yield was observed
when benzaldeyde was used and the Passerini 3-CR product
15 was isolated and characterized (see Supporting Informa-
tion). In this case, imine formation occurred quite readily,
being favored by the conjugation, but slow R-addition of
the isonitrile followed. For substrates with limited reactivity
(aromatic aldehydes and ketones), Lewis acid catalysts have
Table 1. Compounds Obtained by Variation of the Carbonyl
Component
entry
R
Ugi 4CM product P-3CM product
(15) Pirrung, M. C.; Das Sarma, K. J. Am. Chem. Soc. 2004, 126, 444–
445.
1
2
3
4
H-
Pr-
Ph-
8 (51)
-
-
13 (31)
14 (21)
traces
(16) (a) Formica, M.; Fusi, V.; Macedi, E.; Paoli, P.; Piersanti, G.; Rossi,
P.; Zappia, G.; Orlando, P. New J. Chem. 2008, 32, 1204–1214. (b) Ambrosi,
G.; Formica, M.; Fusi, V.; Giorgi, L.; Guerri, A.; Micheloni, M.; Paoli, P.;
Pontellini, R.; Rossi, P. Chem.-Eur. J. 2007, 13, 702–710. (c) Ciampolini,
M.; Dapporto, P.; Micheloni, M.; Nardi, N.; Paoletti, P.; Zanobini, F.
J. Chem. Soc., Dalton Trans. 1984, 1357–1362.
15 (49)
16 (34)
cyclopentanone
(17) Sheng, X.; Lu, X.; Chen, Y.; Lu, G.; Zhang, J.; Shao, Y.; Liu, F.;
Xu, Q. Chem.-Eur. J. 2007, 13, 9703–9712.
also been used.20 The use of 10% quantities of Sc(OTf)3,
Ti(OiPr)4, or Mg(ClO4)2 or molecular sieves did not enhance
the yield of Ugi products.
(18) (a) Yu, J.; Parker, D.; Pal, R.; Poole, R. A.; Cann, M. J. J. Am.
Chem. Soc. 2006, 128, 2294–2299. (b) Kovacs, Z.; Sherry, A. D. J. Chem.
Soc., Chem. Commun. 1995, 185–186.
(19) For uses of 6 and 7 in molecular recognition studies, see: (a)
Ambrosi, G.; Formica, M.; Fusi, V.; Giorgi, L.; Guerri, A.; Lucarini, S.;
Micheloni, M.; Paoli, P.; Rossi, P.; Zappia, G. Inorg. Chem. 2005, 44, 3249–
3261. (b) Haeg, M. E.; Whitlock, B. J.; Whitlock, H. W., Jr. J. Am. Chem.
Soc. 1989, 111, 692–696.
(20) (a) Kusebauch, U.; Beck, B.; Messer, K.; Herdtweck, E.; Do¨mling,
A. Org. Lett. 2003, 5, 4021–4024. (b) Okandeji, B. O.; Gordon, J. R.; Sello,
J. K. J. Org. Chem. 2008, 73, 5595–5597. (c) Wang, S.; Wang, M.; Wang,
D.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47, 388–391.
Org. Lett., Vol. 11, No. 2, 2009
419

The isocyanide and the carboxylic acid components were
also varied, and the results are listed in Table 2. As with the
Table 2. Compounds Obtained by Variation of the Isonitrile and
Acid Component
entry
R1
R2
yield
product
1
2
3
4
5
6
cHex
cHex
cHex
cHex
Bn
Me
Ph
51
49
56
62
53
42
8
17
18
19
20
21
Ph-CHdCH-
CbzNH-CH2-
Me
Me
t-Bu
Figure 2. Proposed mechanism for the N-split-Ugi reaction in a
polyazamacrocyclic system.
parent Ugi 4CR, structural modification of one or both
components did not affect either the progress or the yield of
the corresponding reactions, which were still characterized
by good overall efficiency. Furthermore, entry 4 (Table 2)
exemplifies the synthetic power of this transformation: the
product 19 was obtained using N-protected glycine as the
acid component. This result allowed the peptide-like se-
quence to be extended into the macrocyclic system and
potentially furnish easily homochiral unsymmetrical difunc-
tionalized N1,N7 cyclen in a single step.
In summary, we have developed a new, simple, and
efficient application of the Ugi multicomponent reaction that
allows the one-pot direct preparation of unsymmetrical
polyazamacrocycles, as well as their open-chain counterparts
from readily available compounds. This approach avoids the
time- and chemical-consuming steps necessary to discrimi-
nate the chemically equivalent nitrogen atoms of such
polyamines.21 The enabling methodology presented here will
facilitate the synthesis of novel agents, improve conjugation
efficiency of biopolymers bearing macrocycles to targeting
moieties, and simplify functionalization of agents and
intermediates.
Although no detailed mechanistic studies have been carried
out at this point, a possibile mechanism can be envisaged
based on observed yields and reactivity.
In detail (Figure 2), one of the two secondary amines of
the substrate reacts with the carbonyl group to afford an
iminium ion which reacts via R-addition with the isocyanide
and the carboxylate moiety. The resulting intermediate A
undergoes a subsequent transacylation in which the acyl
moiety migrates to the second N7 secondary amine (Mumm
rearrangement), either directly (path b) and/or through the
intermediate acylated heteroatom I, that acts as a carrier of
the acyl group (path a). The latter statement can be made by
comparing the different reaction conditions used for sub-
strates 4 and 7. The more nucleophilic nitrogen of the
pyridine in compound 7 allows the reaction to take place at
room temperature in 4 h, whereas 4 required refluxing
methanol and 3 days. When cyclen (Z ) NH) is employed,
an equilibrium is present between compounds I and P.
`
Acknowledgment. Financial support from UniversitaI
degli Studi di Urbino “Carlo Bo” and M.I.U.R PRIN 2006
and PRIN 2007, Italy, is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL802674R
(21) For the use of secondary amines in the Ugi 4CR, see: (a) Pirali,
T.; Callipari, G.; Ercolano, E.; Genazzani, A. A.; Giovenzana, G. B.; Tron,
G. C. Org. Lett. 2008, 10, 4199–4202. (b) Bonne, D.; Dekhane, M.; Zhu,
J. Org. Lett. 2004, 6, 4771–4774. (c) Tanaka, Y.; Hasui, T.; Suginome, M.
Org. Lett. 2007, 9, 4407–4410.
420
Org. Lett., Vol. 11, No. 2, 2009