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
`
`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.
`
`9622
`
`J. Org. Chem. 2006, 71, 9622-9627
`
`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
`(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
`
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`Synthesis of Conformationally Preorganized Malonamides
`
`Preorganized 6,6-Bicyclic Malonamides 1 and
`CHART 1.
`the Acyclic Malonamides used as Models (2a and 2d) for the
`Malonamides used in the Diamex Process (2b and 2c)
`
`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.
`(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.
`(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.
`
`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.
`
`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
`
`(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.
`
`J. Org. Chem, Vol. 71, No. 26, 2006 9623
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`SCHEME 1. Reductive Cyclization of a Cyanoester
`Producing a Bicyclic Diamide Based on a Fused Five- and
`Six-Membered Ring System
`
`SCHEME 3 a
`
`Parks et al.
`
`SCHEME 2. Retrosynthetic Analysis Showing Two Possible
`Routes to the Bisfunctionalized 6,6-BMAs Based upon the
`Literature Precedent of the 5,6-BMA
`
`a Reagents and conditions:
`(a) THF, reflux; (b) PPh3, I2, imidazole,
`CH2Cl2; (c) diethyl malonate, NaH, THF, reflux.
`
`SCHEME 4 a
`
`a Reagents and conditions: (a) (i) O3, EtOAc, -78 (cid:176)C, (ii) PPh 3; (b)
`bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride, CH2Cl2;
`(c) (i) O3, EtOAc, 78 (cid:176)C, (ii) H 2 (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.
`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
`obtained in excellent yield with little impurity (by 1H 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
`
`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 (cid:176)C in
`the presence of a stabilizer (copper or hydroquinone) to prevent
`decomposition or used immediately. Refluxing 14 with diethyl
`
`(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
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`Synthesis of Conformationally Preorganized Malonamides
`
`Piperidine Formation from Dialdehyde 10 and
`SCHEME 5.
`a Primary Aminea
`
`Stepwise Ring Closure Used to Investigate the
`SCHEME 7.
`Stereochemistry of the Ring Formationa
`
`a Conditions: (a) (i) 1,2-DCE, octylamine, (ii) NaBH(OAc)3.
`
`SCHEME 6 a
`
`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
`
`reagent
`19a
`19b
`19c
`19d
`19e
`19f
`19g
`19h
`19i
`19j
`
`product
`1a
`1b
`1c
`1d
`1e
`1f
`1g
`1h
`1i
`1j
`
`R
`(CH2)7CH3
`CH3
`(CH2)9CH3
`(CH2)15CH3
`(CH2)2Ph
`(CH2)2OH
`(CH2)4OH
`(CH2)2(CF2)5CF3
`(CH2)2(CF2)7CF3
`(CH2)2COOC2H5
`
`% yield
`
`51
`79
`44
`40
`49
`40
`35
`35
`43
`48
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`
`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.
`
`a The initial cyclization leads to the trans configuration. Formation of
`the second ring always leads to a cis configuration.
`
`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).
`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
`either cis or trans to each other. To our surprise, the 1H 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.
`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
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`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
`by a 4.2 ppm peak in the 1H 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(cid:226)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(cid:226)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(cid:226)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.
`
`Experimental
`
`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 (cid:176)C.
`96% yield. 1H NMR (CDCl3) (cid:228) 5.837 (m, 2H), 5.156 (m, 2H),
`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 (cid:176)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,
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`Parks et al.
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`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 (cid:176)C at 20 mmHg). 14 is indefinitely stable when stored
`at -25 (cid:176) 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) (cid:228) 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) (cid:228) 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.
`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 (cid:176)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 (cid:176)C
`and quenched with water. The layers were separated, and the
`aqueous phase was extracted with ether (2 (cid: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 (cid:176)C at 0.3 mmHg) as a
`colorless oil after a forerun of diethyl malonate. 1H NMR (CDCl3)
`(cid:228) 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) (cid:228) 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 (cid:176)C) yielded 16 as a clear, colorless oil (30.477 g,
`0.135 mol, 99.6% yield). 1H NMR (300 MHz, CDCl3) (cid:228) 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) (cid:228) 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 (cid:176)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
`is carried immediately to the next reaction. 1H NMR (300 MHz,
`CDCl3) (cid:228) 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).
`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 (cid:176)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 ((cid:24)150 mL) and
`quenched with saturated aqueous NaHCO3 (100 mL). The layers
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`IPR2020-00770
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`Synthesis of Conformationally Preorganized Malonamides
`
`were separated, and the organic layer was washed with saturated
`aqueous NaHCO3 (2 (cid: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
`products give similar results in the final reaction. 1H NMR (300
`MHz, CDCl3) (cid:228) 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.
`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 ((cid:24)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 (cid:176)C).
`X-ray quality crystals were grown from ethyl acetate, and subse-
`quent purifications via uranyl precipitation (precipitation is rapid)
`were performed. 1H NMR (CDCl3) (cid:228) 3.30 (m, 5H), 2.95 (s, 6H),
`2.44 (m, 1H), 1.92 (m, 2H), 1.75 (m, 2H). 13C NMR (CDCl3) (cid:228)
`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-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 (cid:176)C). Subse-
`quent purifications via uranyl precipitation (precipitation is slow)
`were performed. 1H NMR (CDCl3) (cid:228) 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) (cid:228) 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;