Convenient synthesis of 6,6-bicyclic malonamides: A new class of conformationally preorganized ligands for f-block ion binding

Article abstract of DOI:10.1021/jo0617262

A general synthetic approach was developed for the preparation of a series of 6,6-bicyclic malonamides, a class of ligands that provide a preorganized binding site for f-block ions (particularly trivalent lanthanides). The approach described is convenient to introduce a variety of functional groups at the amide nitrogens to tune the properties of the ligand without altering the preorganized binding. Each of the ten derivatives (that represent a range of functionality, including R = alkyl, hydroxy, phenyl, ester, perfluorocarbon) reported here derives from a single, readily prepared dialdehyde intermediate. This intermediate is converted to the final products via reductive amination with an appropriately functionalized benzylamine, followed by hydrogenolysis and lactam formation. Because derivatization occurs late in the synthesis, the approach is general, requiring only modification of the purification procedures for each new derivative. To aid in the purification of the bicyclic malonamides, we report a novel complexation-based purification method that takes advantage of the high affinity of the ligand for f-block metals.

Full text of DOI:10.1021/jo0617262

Convenient Synthesis of 6,6-Bicyclic Malonamides: A New Class of
Conformationally Preorganized Ligands for f-Block Ion Binding
Bevin W. Parks, Robert D. Gilbertson,† Dylan W. Domaille,‡ and James E. Hutchison*
Chemistry Department, UniVersity of Oregon, Eugene, Oregon 97403-1253
hutch@uoregon.edu
ReceiVed August 20, 2006
A general synthetic approach was developed for the preparation of a series of 6,6-bicyclic malonamides,
a class of ligands that provide a preorganized binding site for f-block ions (particularly trivalent
lanthanides). The approach described is convenient to introduce a variety of functional groups at the
amide nitrogens to tune the properties of the ligand without altering the preorganized binding. Each of
the ten derivatives (that represent a range of functionality, including R ) alkyl, hydroxy, phenyl, ester,
perfluorocarbon) reported here derives from a single, readily prepared dialdehyde intermediate. This
intermediate is converted to the final products via reductive amination with an appropriately functionalized
benzylamine, followed by hydrogenolysis and lactam formation. Because derivatization occurs late in
the synthesis, the approach is general, requiring only modification of the purification procedures for
each new derivative. To aid in the purification of the bicyclic malonamides, we report a novel
complexation-based purification method that takes advantage of the high affinity of the ligand for f-block
metals.
Introduction
impacting the binding characteristics.1,4 Although new develop-
ments, including computer modeling approaches (e.g., molecular
mechanics strategies such as HostDesigner),5 facilitate the
selection of new targets, each design must still be refined by
coupling modeling studies with synthesis and physical testing.
Each iteration of modeling-synthesis-testing affords a greater
understanding of ligand-metal interactions, improves design
models, and accelerates the transition into de novo ligand
design.
During the last two decades, significant effort has been
directed toward developing design strategies for f-block ion
binders, primarily based upon diamide structures such as the
malonamides. Malonamides were originally chosen for develop-
ment because they are completely incinerable, relatively easy
to synthesize, selective for trivalent lanthanides, stable to
The design and synthesis of ligand architectures that present
an organized array of donor atoms to enhance the interactions
between the ligand and a metal is an important, ongoing
challenge in molecular design.1-3 The type and geometric
arrangement of donor atoms is crucial to controlling the
properties of both the ligand and the resulting metal-ligand
complex.1-3 The application of these new architectures requires
that their designs permit functionalization of the metal-binding
moiety to tune the properties of the ligand without adversely
† Present address: Los Alamos National Laboratory, Los Alamos, NM 87545.
‡ Present address: Department of Chemistry, University of California,
Berkeley, CA 94720.
(1) Hay, B. P.; Gutowski, M.; Dixon, D. A.; Garza, J.; Vargas, R.; Moyer,
B. A. J. Am. Chem. Soc. 2004, 126, 7925-7934.
(2) Hay, B. P.; Nicholas, J. B.; Feller, D. J. Am. Chem. Soc. 2000, 122,
10083-10089.
(3) Lumetta, G. J.; Rapko, B. M.; Garza, P. A.; Hay, B. P.; Gilbertson,
R. D.; Weakley, T. J. R.; Hutchison, J. E. J. Am. Chem. Soc. 2002, 124,
5644-5645.
(4) Clement, O.; Rapko, B. M.; Hay, B. P. Coord. Chem. ReV. 1998,
170, 203-243.
(5) Hay, B. P.; Firman, T. K.; Lumetta, G. J.; Rapko, B. M.; Garza, P.
A.; Sinkov, S. I.; Hutchison, J. E.; Parks, B. W.; Gilbertson, R. D.; Weakley,
T. J. R. J. Alloys Compd. 2004, 374, 416-419.
10.1021/jo0617262 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/02/2006
9622
J. Org. Chem. 2006, 71, 9622-9627

Synthesis of Conformationally Preorganized Malonamides
CHART 1. Preorganized 6,6-Bicyclic Malonamides 1 and
the Acyclic Malonamides used as Models (2a and 2d) for the
Malonamides used in the Diamex Process (2b and 2c)
relative to the acyclic analogues, providing strong support for
our initial premise.3,21-24
To explore the coordination chemistry of this new ligand-
system and prepare ligands that have properties that are tailored
for particular applications, it was necessary to prepare a number
of derivatives. Thus, we aimed to develop a convenient, efficient,
and general approach that could be accomplished in only a few
steps, required limited purifications, and made use of shelf-
stable, common intermediates close to the end of the synthesis.
The design of the synthesis was geared toward easy modification
because one derivative might be the best choice for studying
the solid-state structure of the ligand (e.g., 1b),3,22 whereas
another derivative may be necessary for evaluating the extraction
efficiency (e.g., 1a).3 In addition, it is desirable to manipulate
the physical properties such as solubility or melting point or to
introduce additional functionalization without altering the
structure of the binding moiety. The synthesis was also designed
to be scaleable and efficient because multigram quantities of
material were required for exploring the fundamental coordina-
tion chemistry, comparing the new structures to those of existing
ligand architectures, and further developing the ligands for a
wide variety of applications.
Here, we report the synthesis and purification of a unique
series of 10 functionalized malonamide ligands designed to be
preorganized for chelation of f-block ions. Each derivative can
be accessed through a stable cyclopentene derivative that can
be prepared easily on a large scale. Conversion of this derivative
to a dialdehyde allows introduction of a range of functional
groups through reductive amination. Because derivatization
occurs late in the synthesis, our approach is general for a wide
range of derivatives, only requiring modification of the purifica-
tion process for the final products. Purification is facilitated by
a complexation-based purification method we developed that
takes advantage of the high affinity of the ligand for f-block
metals.
radiolysis, and able to bind in acidic aqueous media.6-10 A large
number of derivatives of the acyclic malonamide substructure
(see, for example, 2a-d in Chart 1) have been prepared with
the aim of improving the extraction characteristics (primarily
the binding characteristics and solubility) for radionuclide
separation (e.g., the DIAMEX (diamide extraction) process for
minor actinide separation).6-8,10-15 The coordination chemistry
and extraction efficiency of these derivatives have been
explored, and the influence of ligand structure (the identity of
the substituents on the amide nitrogens and the central meth-
ylene) upon binding affinity has been described.4,6,9,10,16,17
Despite considerable effort, only modest improvements in the
extraction of trivalent lanthanides have been realized.6-9,11,13,15,18
Our approach to this problem derives from the premise that
preorganization of the malonamide moiety into a conformation
resembling that required in the metal-ligand complex will
enhance the binding interaction.3,19-21 In effect, the strain energy,
which acyclic ligands 2 experience upon chelation to a metal
center, is minimized in the bicyclic ligands 1.3,20-22 Initial studies
with 1a and 1b showed large enhancements in extraction
efficiencies and binding affinities for the bicyclic structures
(6) Chan, G. Y. S.; Drew, M. G. B.; Hudson, M. J.; Iveson, P. B.;
Liljenzin, J.-O.; Skaalberg, M.; Spjuth, L.; Madic, C. J. Chem. Soc., Dalton
Trans. 1997, 649-660.
(7) Charbonnel, M. C.; Daldon, M.; Berthon, C.; Presson, M. T.; Madic,
C.; Moulin, C. SolVent Extraction for the 21st Century, Proceedings of ISEC,
Barcelona, Spain, July 11-16, 1999; Society of Chemical Industry, London,
2001; Vol. 2, pp 1333-1338.
Results and Discussion
To obtain the desired 6,6-bicyclicmalonamide (BMA) in
quantities sufficient for use in physical studies and potential
applications, we aimed for the synthesis to be general to multiple
functionalities and high yielding, with few steps and minimal
purifications. Surprisingly, few examples of BMAs are found
in the literature.25 The synthesis of a representative example,
an unsubstituted 5,6-BMA with a cis ring junction, 5, is shown
in Scheme 1.25 Although this approach was not directly
extendable to our targets, the synthesis provides the basis for
the retrosynthetic analysis of our desired 6,6-BMA.
Upon the basis of this precedent, the bisfunctionalized 6,6-
bicyclic malonamide (R2BMA, 1) could be prepared by in-
tramolecular ring closing of the bisamine 6 shown in Scheme
2. Bisamine 6 might be obtained through either of two routes.
These routes differ mainly in whether the coupling to diethyl
malonate occurs before or after the incorporation of the amine
(8) Charbonnel, M. C.; Flandin, J. L.; Giroux, S.; Presson, M. T.; Madic,
C.; Morel, J. P. International SolVent Extraction Conference; Cape Town,
South Africa, March 17-21, 2002; South African Institute of Mining and
Metallurgy, Johannesburg, 2002; pp 1154-1160.
(9) McNamara, B. K.; Lumetta, G. J.; Rapko, B. M. SolVent Extr. Ion
Exch. 1999, 17, 1403-1421.
(10) Rao, L.; Zanonato, P.; Di Bernardo, P.; Bismondo, A. J. Chem.
Soc., Dalton Trans. 2001, 1939-1944.
(11) Bao, M.; Sun, G.-X. J. Radioanal. Nucl. Chem. 1998, 231, 203-
205.
(12) Berthon, L.; Morel, J. M.; Zorz, N.; Nicol, C.; Virelizier, H.; Madic,
C. Sep. Sci. Technol. 2001, 36, 709-728.
(13) Hubert, H.; Musikas, C. European Patent Application, Commissariat
a l’Energie Atomique, Fr., Ep, 1984; p 25.
(14) Kumbhare, L. B.; Prabhu, D. R.; Mahajan, G. R.; Sriram, S.;
Manchanda, V. K.; Badheka, L. P. Nucl. Technol. 2002, 139, 253-262.
(15) Spjuth, L.; Liljenzin, J. O.; Skaalberg, M.; Hudson, M. J.; Chan,
G. Y. S.; Drew, M. G. B.; Feaviour, M.; Iveson, P. B.; Madic, C. Radiochim.
Acta 1997, 78, 39-46.
(16) Rapko, B. M.; McNamara, B. K.; Rogers, R. D.; Broker, G. A.;
Lumetta, G. J.; Hay, B. P. Inorg. Chem. 2000, 39, 4858-4867.
(17) Rapko, B. M.; McNamara, B. K.; Rogers, R. D.; Lumetta, G. J.;
Hay, B. P. Inorg. Chem. 1999, 38, 4585-4592.
(18) Falana, O. M.; Koch, H. F.; Roundhill, D. M.; Lumetta, G. J.; Hay,
B. P. Chem. Commun. 1998, 503-504.
(19) Hay, B. P.; Clement, O.; Sandrone, G.; Dixon, D. A. Inorg. Chem.
1998, 37, 5887-5894.
(22) Parks, B. W.; Gilbertson, R. D.; Hutchison, J. E.; Healey, E. R.;
Weakley, T. J. R.; Rapko, B. M.; Hay, B. P.; Sinkov, S. I.; Broker, G. A.;
Rogers, R. D. Inorg. Chem. 2006, 45, 1498-1507.
(23) Sinkov, S. I.; Rapko, B. M.; Lumetta, G. J.; Hay, B. P.; Hutchison,
J. E.; Parks, B. W. Inorg. Chem. 2004, 43, 8404-8413.
(24) Sinkov, S. I.; Rapko, B. M.; Lumetta, G. J.; Hutchison, J. E.; Parks,
B. W. AIP Conference Proceedings, 2003; Vol. 673, pp 36-38.
(25) Altomare, C.; Carotti, A.; Casini, G.; Cellamare, S.; Ferappi, M.;
Gavuzzo, E.; Mazza, F.; Pantaleoni, G.; Giorgi, R. J. Med. Chem. 1988,
31, 2153-2158.
(20) Hay, B. P.; Gutowski, M.; Dixon, D. A.; Garza, J.; Vargas, R.;
Moyer, B. A. J. Am. Chem. Soc. 2004, 126, 7925-7934.
(21) Lumetta, G. J.; Rapko, B. M.; Hay, B. P.; Garza, P. A.; Hutchison,
J. E.; Gilbertson, R. D. SolVent Extr. Ion Exch. 2003, 21, 29-39.
J. Org. Chem, Vol. 71, No. 26, 2006 9623

Parks et al.
SCHEME 1. Reductive Cyclization of a Cyanoester
Producing a Bicyclic Diamide Based on a Fused Five- and
Six-Membered Ring System
SCHEME 3a
a Reagents and conditions: (a) THF, reflux; (b) PPh3, I2, imidazole,
CH2Cl2; (c) diethyl malonate, NaH, THF, reflux.
SCHEME 2. Retrosynthetic Analysis Showing Two Possible
Routes to the Bisfunctionalized 6,6-BMAs Based upon the
Literature Precedent of the 5,6-BMA
SCHEME 4a
a Reagents and conditions: (a) (i) O3, EtOAc, -78 °C, (ii) PPh3; (b)
bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride, CH2Cl2;
(c) (i) O3, EtOAc, 78 °C, (ii) H2 (30 psi), 5% Pd/carbon.
malonate and NaH in THF over a period of several days afforded
15 in 95% yield. Although the rates of enolate substitutions,
such as the one shown here, are enhanced in the presence of a
polar aprotic solvent such as DMSO, in this case, THF was
preferred because it prevents formation of a side product
believed to result from O-alkylation of the malonate ester.
Ozonolysis and Reduction to Dialdehyde 9. Early attempts
to convert diene 15 to dialdehyde 9 directly via ozonolysis with
a reductive workup (Scheme 4, a) were problematic. Neither
dimethyl sulfide nor catalytic hydrogenation readily reduces the
ozonide intermediate, possibly due to the formation of bisper-
oxide or oligomeric species instead of the typical ozonide
following fragmentation of the initial ozone adduct. Triph-
enylphosphine effected the reduction of the ozonolysis inter-
mediate, but separation of the produced triphenylphosphine
oxide from the product was troublesome.
functionality. In route A, diethyl glutarate 8 is converted to a
bisamide that is subsequently reduced to the bisamine. Once
the hydroxyl is transformed to a good leaving group, 7 is then
coupled to diethyl malonate to form 6. For route B, diene 10 is
coupled to diethyl malonate and the alkenes oxidize to form
dialdehyde intermediate 9. Dialdehyde 9 is then transformed to
6 via reductive amination. Route B was ultimately chosen
because route A is complicated by intramolecular reactions
involving displacement of the leaving group, X, by the amines
to form an azetidine and because route B offers several desirable
attributes. It allows us to add the amine functionality later in
the reaction sequence, provides more shelf-stable intermediates,
and has overall fewer transformationsssynthesis of the dial-
dehyde 9, reductive amination to form 6, and ring closing to
the product 1.
Preparation of the Diene 15. Our first target, dialdehyde 9,
should be readily obtained through the reaction of ozone with
diethyl malonate-diene 15. Large quantities (30 g) of 15 can be
synthesized in excellent yield over three steps (Scheme 3).
Although 1,6-heptadien-4-ol 13 is commercially available, it is
convenient (and inexpensive) to prepare at a large scale via the
high-yielding Grignard reaction of allyl bromide with ethyl
formate. Alcohol 13 was then converted to iodide 14 by standard
methods in good yield.26 Iodide 14 can be stored at -20 °C in
the presence of a stabilizer (copper or hydroquinone) to prevent
decomposition or used immediately. Refluxing 14 with diethyl
All of these problems were overcome by adding a step to
the reaction sequence. Ring-closing metathesis (RCM) of diene
15 with Grubbs’ catalyst (bis(tricyclohexylphosphine) benzy-
lidine ruthenium(IV) dichloride)27 produced the cyclopentene
ring (Scheme 4, b) of 16 quantitatively within 30 min. When
olefin 16 is treated with ozone at low temperature, it reacts
quantitatively to give the ozonide, which is easily reduced to 9
by catalytic hydrogenation (Scheme 4, c). Dialdehyde 9 was
1
obtained in excellent yield with little impurity (by H NMR)
and was carried forward to the next reaction in crude form after
vacuum filtration to remove the Pd/C catalyst.
The RCM was initially performed only on a 5 mmol scale,
and 16 was used in crude form; therefore, the main contaminant
in 9 was the catalyst. It has since been found that the RCM on
a 0.2 mol scale requires only slightly more catalyst than the
small-scale reaction. The larger amount of product from the
scale-up also made it possible to distill cyclopentene 16 away
(26) Hoarau, S.; Fauchere, J. L.; Pappalardo, L.; Roumestant, M. L.;
Viallefont, P. Tetrahedron: Asymmetry 1996, 7, 2585-2593.
(27) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783-3784.
9624 J. Org. Chem., Vol. 71, No. 26, 2006

Synthesis of Conformationally Preorganized Malonamides
SCHEME 5. Piperidine Formation from Dialdehyde 10 and
a Primary Aminea
SCHEME 7. Stepwise Ring Closure Used to Investigate the
Stereochemistry of the Ring Formationa
a The initial cyclization leads to the trans configuration. Formation of
the second ring always leads to a cis configuration.
a Conditions: (a) (i) 1,2-DCE, octylamine, (ii) NaBH(OAc)3.
SCHEME 6a
give bistertiary amine 20. Diamine 20 was purified to remove
excess secondary amine 19, though it was not necessary because
use of the crude material in a repeated experiment did not hinder
the yield of the following reactions nor alter the purification of
the final product. The benzyl-protecting groups were removed
via catalytic hydrogenolysis to form bis-secondary amine 6. The
close proximity of the amines to the esters and the favorable
ring size of the product resulted in spontaneous lactam forma-
tion, even before reflux. In fact, a derivative of 6 was only
isolated in one instance (see Supporting Information). Heating
to reflux in absolute ethanol for 2-18 h afforded 1 in overall
good yield (see Table 1).
a Reaction conditions: (a) (i) benzyl amine 19, (ii) NaBH(OAc)3, 1,2-
DCE; (b) H2 (50 psi), 20% Pd(OH)2/carbon, EtOH; (c) EtOH, reflux.
TABLE 1. Reagents Used and Isolated Yields (from Cyclopentene
16) in the Preparation of Malonamides 1
Attempts to Prepare the trans-6,6-BMA. It was expected
that the synthetic method would produce a mixture of stereoi-
somers, with the hydrogens on the bridgehead carbons being
reagent
product
R
% yield
1
2
3
4
5
6
7
8
9
19a
19b
19c
19d
19e
19f
19g
19h
19i
1a
1b
1c
1d
1e
1f
1g
1h
1i
(CH2)7CH3
CH3
(CH2)9CH3
(CH2)15CH3
(CH2)2Ph
(CH2)2OH
(CH2)4OH
(CH2)2(CF2)5CF3
(CH2)2(CF2)7CF3
(CH2)2COOC2H5
51
79
44
40
49
40
35
35
43
48
1
either cis or trans to each other. To our surprise, the H NMR
indicated only one stereoisomer (see Supporting Information),
and multiple crystal structures have shown evidence of only
the cis structure.22 Molecular mechanics indicates that both
stereoisomers are preorganized for metal ion binding, though
the trans stereoisomer of 1 is ideally preorganized and the cis
stereoisomer must undergo slight rearrangement upon binding.3
The ideal conformation of the trans stereoisomer should lead
to further enhanced binding and extraction properties, so the
ring closing was further examined.
Using a model compound to study the ring-closing reactions
that lead to the bicyclic system, we have found that the
substituents on the monocyclic amide have a trans relationship
to each other upon closure of the first ring (Scheme 7). When
aldehyde 21 was treated with an excess of phenethylamine and
NaBH(OAc)3 in 1,2-dichloroethane (DCE), amide 22 was
produced (along with a small amount of material in which the
amine had been alkylated by 2 equiv of the aldehyde). The trans
relationship of the ring substituents in 22 was established by
the magnitude of the J3 coupling constant of 10 Hz between
the bridgehead protons (a cis relationship of these protons would
be expected to exhibit a smaller J3 coupling constant).
Yet, closure of the second ring consistently leads to the cis
product. It is possible that the trans stereoisomer cannot adopt
a conformation that allows the amine to attack the ester, but
epimerization to the cis conformation allows the ring-closing
amide formation to occur. Another possible explanation is that
the ideal binding conformation of trans-1, demonstrated by
intersecting carbonyl dipoles,3 leads to a dipole-dipole interac-
tion that is unfavorable. This interaction could be enough to
shift the equilibrium of the epimerization to the cis conformation
of 1. In any case, this type of approach does not appear to be
viable for synthesis of the trans conformation of 1.
10
19j
1j
from the residual catalyst without loss of yield (99.6% isolated
yield). The increased purity of 16 increases the reaction rates
of both the ozonolysis and catalytic hydrogenation and increases
the stability of 9.
Synthesis of Bicyclic Malonamides via Reductive Amina-
tion and Lactam Formation. We found it convenient to add
the desired functionality of the BMA via reductive amination
of the dialdehyde. Although it was expected that dialdehyde 9
could be reacted with an excess of amine to give the desired
bisamine intermediate 6, reaction of primary amines with 9
results in formation of piperidine 18 (Scheme 5). The intramo-
lecular reaction of the second aldehyde with the secondary amine
in intermediate 17 is much faster than the intermolecular reaction
with the second equivalent of primary amine even when a large
excess of the amine is used. The use of benzyl-protected amines
eliminates this problem. Benzyl-protected amines that are not
commercially available can be synthesized from the correspond-
ing amines or iodides (see Supporting Information).28-30
Various derivatives of 1 have been synthesized with no
change to the reaction conditions (Scheme 6) and were isolated
in good yields (Table 1). A modest excess (2.2 mol equiv) of
benzyl-protected amine 19 was added to 9, and the intermediate
was then reduced to the amine by addition of NaBH(OAc)3 to
(28) Szonyi, F.; Cambon, A. J. Fluorine Chem. 1989, 42, 59-68.
(29) Moore, J. D.; Byrne, R. J.; Vedantham, P.; Flynn, D. L.; Hanson,
P. R. Org. Lett. 2003, 5, 4241-4244.
(30) Petrova, D. S.; Penner, H. P. Croat. Chem. Acta 1968, 40, 189-
94.
Purification Strategies for Functionalized BMAs. The
diversity of BMA 1 functionality has necessitated the develop-
ment of several purification strategies, including Kugelrohr
distillation and complex-mediated precipitation in addition to
J. Org. Chem, Vol. 71, No. 26, 2006 9625

Parks et al.
and the resulting brown slurry was poured into rapidly stirred ether
(500 mL). The precipitated solids were removed by vacuum
filtration through a pad of Celite, and the filter cake was washed
with ether (50 mL). The remaining solvent was removed by rotary
evaporation, and distillation of the residue (in the presence of
hydroquinone or copper) provided 37.8 g (76.3%) of colorless liquid
(bp 65-70 °C at 20 mmHg). 14 is indefinitely stable when stored
at -25 °C over copper; however, rapid discoloration was observed
when the compound was allowed to stand at room temperature with
no inhibitor present. 1H NMR (CDCl3) δ 5.81 (m, 2H), 5.18-5.10
(m, 4H), 4.08 (pentet, J ) 6.5 Hz, 1H), 2.62 (t, J ) 6.5 Hz, 4H).
13C NMR (CDCl3) δ 136.1, 117.8, 43.9, 34.2. Anal. Calcd for
C7H11I: C, 37.86; H, 4.99. Found: C, 38.06; H, 5.13.
recrystallization and chromatography. No single technique for
purification worked for all synthesized derivatives. The main
impurities in the final product 1 were benzylamine 19, the
corresponding primary amine, and an ethyl ester characterized
1
by a 4.2 ppm peak in the H NMR. It seems likely that this
ester is incompletely cyclized 1. Although many of the deriva-
tives of 1 are solids, recrystallization was not a consistent
method of purification. Owing to differences in impurity profiles
and the low melting points of some of the derivatives,
recrystallization was time-consuming and often unsuccessful
(crystals were often contaminated with the ester-amide side
product). The remaining derivatives of 1 are oils, and purifica-
tion via chromatography was also problematic. Kugelrohr
distillation has been used in the case of the octyl derivative,
but the temperature must be closely monitored and carefully
controlled to avoid decomposition.
We have developed a purification strategy that is reliable,
convenient, and broadly applicable that exploits the strong
binding of the whole class of ligands to f-block metal ions. This
method has been applied successfully to the majority of the
derivatives described here (with the exception of the alcohol
derivatives) and is especially advantageous when purifying
derivatives that are low-melting solids or oils. It is less sensitive
than the other methods to varying impurity profiles, making it
a rapid and general method for isolating new derivatives. The
higher selectivity of the desired product for uranyl binding
relative to all other byproducts permits one to isolate derivatives
of 1 from complex reaction mixtures very quickly.
Binding to uranyl nitrate (UO2(NO3)2‚6H2O) is fast in MeOH
and results in a precipitate of the desired product bound to the
uranyl ion. This precipitate can be washed with MeOH to
remove impurities which cannot bind the metal ion, such as
benzylamine 19 or the ester-amide which did not undergo the
second lactam formation to become 1. The solid, dried UO2‚1
complex is then stirred with a 0.1 M aqueous EDTA solution
(pH 8.0). EDTA binds the uranyl much more tightly than BMA
1, and the resulting UO2‚EDTA complex is too polar to be
extracted from the aqueous solution. Extraction with CHCl3
removes 1, the only remaining organic compound, from the
aqueous solution. Evaporation of the dried solution typically
results in a high-purity, colorless oil or solid.
In summary, we have demonstrated a convenient synthetic
method for a range of BMA derivatives where the R groups
are identical. Work is currently underway to modify the synthetic
method, extending it to a variety of BMAs with nonequivalent
R groups. This would be useful to introduce multiple (different)
functionalities into the BMA, making it easier to incorporate
the molecules into functional materials.
Diethyl 2-(4-(1,6-Heptadiene)) Malonate (15). Diethyl malonate
(40.1 g, 0.250 mol) was dissolved in THF (750 mL) and cooled to
0 °C. Solid sodium hydride (5.67 g, 0.236 mol) was slowly added,
and the flask was warmed to ambient temperature. After stirring
for 1 h, 14 (37.0 g, 0.167 mol) was added and the reaction was
stirred at reflux for 5 days. The reaction was then cooled to 0 °C
and quenched with water. The layers were separated, and the
aqueous phase was extracted with ether (2 × 100 mL). The
combined organics were washed with 10% NaOH (100 mL) and
brine (100 mL), then dried (MgSO4) and filtered through Celite.
Solvents were removed by rotary evaporation, and the resulting
oil was distilled to yield 42.4 g (94.8%) of diethyl(4-(1,6-
heptadiene)) malonate 15 (bp 103-105 °C at 0.3 mmHg) as a
colorless oil after a forerun of diethyl malonate. 1H NMR (CDCl3)
δ 5.74 (m, 2H), 5.07-5.00 (m, 4H), 4.20 (q, J ) 7.0 Hz, 4H),
3.42 (d, J ) 7.3 Hz, 1H), 2.34-2.11 (m, 5H), 1.26 (t, J ) 7.0 Hz,
6H). 13C NMR (CDCl3) δ 168.8, 135.7, 117.4, 61.2, 54.3, 37.6,
35.1, 14.1. IR (neat) cm-1 3077, 2981, 1753, 1732. Anal. Calcd
for C14H22O4: C, 66.12; H, 8.72. Found: C, 65.86; H, 8.43.
Diethyl 2-Cyclopent-3-enylmalonate (16). Bis(tricyclohexyl-
phosphine)benzylidine ruthenium(IV) dichloride (10-15 mg) was
added to a solution of 15 (34.403 g, 0.135 mol) in distilled meth-
ylene chloride. Immediate bubbling was observed as the produced
ethylene escaped. Two additional portions of catalyst were added
when the bubbling ceased (ca. 15 min intervals). The reaction
mixture was allowed to stir for 2 h and then concentrated in vacuo
to yield a dark brown oil. Purification via vacuum distillation (180
mTorr, bp 97 °C) yielded 16 as a clear, colorless oil (30.477 g,
1
0.135 mol, 99.6% yield). H NMR (300 MHz, CDCl3) δ 5.63
(s, 2H), 4.20 (m, 4H), 3.18 (d, 1H), 2.92 (m, 1H), 2.58 (dd, 2H),
2.14 (dd, 2H), 1.24 (m, 6H). 13C NMR (CDCl3) δ 168.9, 129.4,
61.1, 57.1, 36.9, 36.8, 14.0. Anal. Calcd for C12H18O4: C, 63.70;
H, 8.02. Found: C, 63.46; H, 8.14.
Diethyl 2-(3-Pentan-1,5-dial) Malonate (9). Pure 16 (5.928 g,
0.0262 mol) was dissolved in ethyl acetate (50 mL) and cooled to
-78 °C. Ozone was passed through the solution until a blue color
persisted. Excess ozone was removed by purging the solution with
N2 as it was warmed to room temperature. Hydrogenation was
carried out at ambient temperature at a H2 pressure of 30 psi with
5% Pd on the carbon catalyst (150 mg). After 5 min, hydrogen
consumption had ceased, at which point the suspension was filtered
through Celite and freed of solvent by rotary evaporation. 9
decomposes rapidly under ambient conditions, so the crude product
Experimental
1
The general experimental conditions and synthesis of all previ-
ously reported compounds are given in the Supporting Information.
1,6-Heptadiene-4-ol (13). Clear, colorless oil. Bp 150-151 °C.
is carried immediately to the next reaction. H NMR (300 MHz,
CDCl3) δ 9.75 (s, 2H), 4.22 (m, 4H), 3.63 (d, 1H), 3.25 (m, 1H),
2.60-2.90 (dq, 4H), 1.24 (t, 6H).
1
96% yield. H NMR (CDCl3) δ 5.837 (m, 2H), 5.156 (m, 2H),
General Procedure for the Preparation of the Bis-3-amine
Diethyl Malonate 20 Based on the Methyl Derivative (20b). To
a solution of 9 (6.767 g, 0.026 mol, assuming 100% yield in the
previous step) in 1,2-dichloroethane (DCE) (150 mL) was added
benzylmethylamine 19b (7.028 g, 0.058 mol, 2.2 equiv). The bright
yellow reaction mixture was cooled to 0 °C, and NaBH(OAc)3
(12.845 g, 0.058 mol, 2.2 equiv) was added slowly (ca. 30 min),
then allowed to warm to room temperature and stir overnight. The
reaction mixture was diluted with ethyl acetate (∼150 mL) and
quenched with saturated aqueous NaHCO3 (100 mL). The layers
5.112 (triplet, J ) 0.9 Hz, 2H), 3.711 (tt, JS ) 5.1 Hz, JL ) 7.5
Hz, 1H), 2.14-2.34 (m, 4H). Anal. Calcd for C7H12O: C, 74.95;
H, 10.78. Found: C, 74.83; H, 11.02.
4-Iodo-1,6-heptadiene (14). Triphenylphosphine (70.0 g, 0.267
mol), imidazole (18.2 g, 0.267 mol), and 13 (25.0 g, 0.223 mol)
were dissolved in dichloromethane (500 mL) and cooled to 0 °C.
Iodine crystals (67.5 g, 0.266 mol) were slowly added (ca. 30 min),
then the reaction was allowed to stir at ambient temperature for 6
h. Most of the dichloromethane was removed by rotary evaporation,
9626 J. Org. Chem., Vol. 71, No. 26, 2006

Synthesis of Conformationally Preorganized Malonamides
were separated, and the organic layer was washed with saturated
aqueous NaHCO3 (2 × 100 mL) and brine (100 mL), dried over
MgSO4, filtered through celite, and concentrated in vacuo. Purifica-
tion through a 1 in. plug of silica gel with 1:1 hexanes/ethyl acetate
(300 mL) to yield 20b as a yellow oil (10.436 g, 0.022 mol, 85%
yield from cyclopentene 16) is optional as the crude and purified
[0.2 g of crude product on a 2 mm silica plate eluted with 5:3
CHCl3/MeOH (100 mL) followed by 10:6:1 CHCl3/MeOH/NH4-
OH(aq) (150 mL) ] and trituration with hexanes and obtained as a
pale yellow viscous oil.
3,9-Diaza-3,9-bis(4-hydroxybutyl)bicyclo[4.4.0]decane-2,10-
dione (1g). 1g was purified by thin-layer rotary chromatography
[0.2 g of crude product on a 2 mm silica plate eluted with 9:1
CHCl3/MeOH (200 mL) followed by 10:6:1 CHCl3/MeOH/NH4-
1
products give similar results in the final reaction. H NMR (300
MHz, CDCl3) δ 7.18-7.30 (m, 10H), 4.14 (q, 4H), 3.55 (d, 1H),
3.41 (obs. m, 1H), 3.40 (s, 4H), 2.35 (t, 4H), 2.13 (s, 6H), 1.58 (m,
4H), 1.21 (t, 6H).
General Procedure for the Preparation of 1. All derivatives
were synthesized in the same manner; however, purifications are
unique and so are listed with the characterization data.
1
OH(aq) (200 mL) ] and obtained as a viscous yellow oil. H NMR
(CDCl3) δ 3.65 (m, 6H), 3.31 (m, 5H), 3.22 (m, 2H), 3.01 (bs,
-OH), 2.48 (dq, Jq ) 2.7 Hz, Jd ) 6.0 Hz, 1H), 1.99 (dq, Jd ) 5.4
Hz, Jq ) 13.8 Hz, 2H), 1.52-1.73 (m, 10H). 13C NMR (CDCl3) δ
166.8, 62.0, 50.1, 46.6, 45.4, 30.2, 29.4, 27.0, 23.6.
3,9-Diaza-3,9-dimethylbicyclo[4.4.0]decane-2,10-dione (1b).
Diamine 20b (2.51 g, 5.4 mmol) was dissolved in absolute ethanol
in a Parr hydrogenation flask, and 20% palladium hydroxide on
charcoal (0.15 g) was added. Hydrogenolysis of the benzyl groups
was carried out at 55 psi until H2 uptake had ceased (∼6 h). The
suspension was then filtered through Celite to remove the catalyst,
and the ethanolic solution was refluxed for 2 h. Removal of solvent
by rotary evaporation followed by preparative radial thin-layer
chromatography (2 mm rotor, methanol/ethyl acetate) provided
0.985 g (5.0 mmol, 93%) of a colorless solid (mp 108-110 °C).
X-ray quality crystals were grown from ethyl acetate, and subse-
quent purifications via uranyl precipitation (precipitation is rapid)
3,9-Diaza-3,9-bis(1H,1H,2H,2H-perfluorooctyl) Bicyclo[4.4.0]-
decane-2,10-dione (1h). 1h was purified by precipitation from
EtOH/H2O and obtained as a white powder (mp 114.6-115.4 °C).
1H NMR (CDCl3) δ 3.63 (t, J ) 6.9 Hz, 4H), 3.38 (m, 5H), 2.32-
2.53 (m, 5H), 2.00 (dq, JS ) 5.4 Hz, JL ) 13.8 Hz, 2H), 1.72 (m,
2H). 13C NMR (CDCl3) d 166.3, 50.2, 46.5, 40.7, 30.4, 28.9, 28.6,
28.3, 26.6. Anal. Calcd for C24H18F26N2O2: C, 33.50; H, 2.11; N,
3.26. Found: C, 33.49; H, 2.07; N, 3.31.
3,9-Diaza-3,9-bis(1H,1H,2H,2H-perfluorodecyl)bicyclo[4.4.0]-
decane-2,10-dione (1i). 1i was purified by precipitation from EtOH/
1
H2O and obtained as a white powder (mp 156.8-157.5 °C). H
NMR (CDCl3) δ 3.64 (m, J ) 6.6 Hz, 4H), 3.39 (t, J ) 6.6 Hz,
5H), 2.34-2.54 (m, 5H), 2.01 (dq, JS ) 5.4 Hz, JL ) 13.8 Hz,
2H), 1.73 (dq, JS ) 7.5 Hz, JL ) 13.5 Hz, 2H). Anal. Calcd for
C28H18F34N2O2: C, 31.71; H, 1.71; N, 2.64. Found: C, 31.44; H,
1.63; N, 2.92.
1
were performed. H NMR (CDCl3) δ 3.30 (m, 5H), 2.95 (s, 6H),
2.44 (m, 1H), 1.92 (m, 2H), 1.75 (m, 2H). 13C NMR (CDCl3) δ
166.2, 50.1, 47.5, 34.67, 31.0, 26.0. IR (KBr) 3439 (broad), 2929,
1651 cm-1. Anal. Calcd for C10H16N2O2: C, 61.20; H, 8.22; N,
14.27. Found: C, 60.94; H, 7.97; N, 14.11.
3,9-Diaza-3,9-bis(2-ethoxycarbonylethyl)bicyclo[4.4.0]decane-
2,10-dione (1j). 1j was purified by uranyl precipitation and obtained
3,9-Diaza-3,9-dioctylbicyclo[4.4.0]decane-2,10-dione (1a). 1a
was purified by Kugelrohr distillation followed by low-temperature
recrystallizations from pentane. It was obtained as a colorless oil
and crystallizes below room temperature (mp 22-24 °C). Subse-
quent purifications via uranyl precipitation (precipitation is slow)
were performed. 1H NMR (CDCl3) δ 3.32 (m, 9H), 2.44 (m, 1H),
1.9-2.1 (m, 2H), 1.65 (m, 2H), 1.52 (m, 4H), 1.26 (m, 20H), 0.89
(t, J ) 6.6 Hz, 6H). 13C NMR (CDCl3) δ 166.2, 50.1, 47.2, 45.3,
31.7, 30.2, 29.2, 27.2, 27.1, 26.9, 22.5, 22.2, 14.0. Anal. Calcd for
C24H44N2O2: C, 73.42; H, 11.30; N, 7.14. Found: C, 73.16; H,
11.25; N, 7.06.
3,9-Diaza-3,9-didecylbicyclo[4.4.0]decane-2,10-dione (1c). 1c
was recrystallized from pentane and obtained as a white powder
(mp 46.8-47.5 °C). 1H NMR (CDCl3) δ 3.21-3.42 (m, 9H), 2.44
(m, 1H), 1.95 (m, 2H), 1.66 (m, 2H), 1.52 (m, 4H), 1.25 (m, 28H),
0.89 (t, J ) 6.6 Hz, 6H). 13C NMR (CDCl3) δ 166.2, 50.2, 47.2,
45.3, 31.8, 29.5, 29.3, 29.2, 27.3, 27.1, 26.9, 22.6, 14.1. Anal. Calcd
for C24H28N2O2: C, 74.95; H, 11.68; N, 6.24. Found: C, 75.01;
H, 12.01; N, 6.13.
3,9-Diaza-3,9-dihexadecylbicyclo[4.4.0]decane-2,10-dione (1d).
1d was recrystallized from n-hexane and obtained as a white powder
(mp 75.6-76.8 °C). 1H NMR (CDCl3) δ 3.20-3.43 (m, 9H), 2.44
(m, 1H), 1.96 (m, 2H), 1.66 (m, 2H), 1.52 (m, 4H), 1.24 (bs, 56H),
0.88 (t, J ) 6.6 Hz, 6H). 13C NMR (CDCl3) δ 166.2, 50.2, 47.2,
45.4, 31.9, 29.66, 29.62, 29.56, 29.52, 29.36, 29.32, 27.3, 27.2,
26.9, 22.6, 14.1. Anal. Calcd for C40H76N2O2: C, 77.86; H, 12.41;
N, 4.54. Found: C, 77.58; H, 12.18; N, 4.42.
1
as a pale yellow crystalline solid (mp 71.8-73.0 °C). H NMR
(CDCl3) δ 4.10 (q, J ) 7.2 Hz, 4H), 3.60 (m, 4H), 3.37 (dd, JS )
5.4 Hz, JL ) 7.2 Hz, 4H), 3.25 (m, 1H), 2.62 (td, JS ) 3.0 Hz, JL
) 6.6 Hz, 4H), 2.41 (m, 1H), 1.93 (dq, JS ) 5.4 Hz, JL ) 13.8 Hz,
2H), 1.64 (dq, JS ) 7.8 Hz, JL ) 13.5 Hz, 2H), 1.23 (t, J ) 6.9
Hz). 13C NMR (CDCl3) δ 172.2, 166.4, 60.5, 50.2, 46.6, 43.8, 32.5,
30.3, 27.0, 14.1. Anal. Calcd for C18H28N2O6: C, 58.68; H, 7.66;
N, 7.60. Found: C, 58.91.; H, 7.61; N, 7.51.
General Procedure for Uranyl Precipitation Purification of
BMA Ligands. A 2 mL methanolic solution of crude Me2BMA
1b (150 mg, maximum of 0.76 mmol) was added to a 2 mL
methanolic solution of uranyl nitrate (UO2(NO3)2‚H2O, 384 mg,
0.76 mmol). The resulting yellow precipitate (forms immediately)
was recovered, washed with MeOH (10 mL), and stirred with 0.5
M EDTA (aqueous, pH 8.0, 5 mL) for 30 min. This solution was
extracted with CHCl3 (6 × 15 mL), and the organics were combined
and concentrated to give Me2BMA 1b as a white crystalline solid
(71 mg, 48% yield from crude product). [Oct2BMA 1a (500 mg,
maximum of 1.27 mmol) yielded a colorless viscous oil (356 mg,
71% yield from crude product).] This method was not attempted
with any derivative of 1 that gave a readily purified solid (1c, 1d,
1h, 1i) and failed with the alcohols (1e, 1f).
Acknowledgment. The authors thank the National Science
Foundation (CHE-0213563) and the NSF IGERT (DGE-
0114419) for financial support.
3,9-Diaza-3,9-bis(2-phenethyl) Bicyclo[4.4.0]decane-2,10-dione
(1e). 1e was purified by uranyl precipitation (precipitation is slow,
aided by addition of 3 Å molecular sieves) and obtained as a pale
Supporting Information Available: Experimental procedures
for the synthesis of 13 and 19; attempted synthesis toward acid-
functionalized 1; 1H NMR, 13C NMR, and EA of propionic acid 6
1
yellow solid (mp 58.9-62.1 °C). H NMR (CDCl3) δ 7.15-7.32
(m, 10H), 3.60 (qt, Jt ) 7.5 Hz, Jq ) 13.5 Hz, 4H), 3.28 (d, J )
6.5 Hz, 1H), 3.08 (m, 4H), 2.91 (t, J ) 7.5 Hz), 2.34 (m, JS ) 5.4
Hz, JL ) 8.4 Hz, 1H), 1.79 (dq, Jq ) 5.4 Hz, Jd ) 13.8 Hz, 2H),
1.49 (dq, Jd ) 6.3 Hz, Jq ) 8.4 Hz, 2H). 13C NMR (CDCl3) δ
166.2, 133.2, 128.9, 128.4, 126.3, 50.2, 49.5, 46.4, 33.6, 30.2, 26.7.
3,9-Diaza-3,9-bis(2-hydroxyethyl) Bicyclo[4.4.0]decane-2,10-
dione (1f). 1f was purified by thin-layer rotary chromatography
1
with experimental details; spectroscopic analysis of 1; H NMR
spectra of 1b in CDCl3 and D2O for reference; 1H NMR spectra of
1e-g for proof of purity. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0617262
J. Org. Chem, Vol. 71, No. 26, 2006 9627