Synthesis of Azacrown Macrocycles and Related Compounds by a

Bis(R-chloroamide)s look like crabs with two reactive claws so the method is called the crablike cyclization reaction. This cyclization strategy has b...
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Ind. Eng. Chem. Res. 2000, 39, 3499-3507

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Synthesis of Azacrown Macrocycles and Related Compounds by a Crablike Cyclization Method: A Short Review Krzysztof E. Krakowiak† and Jerald S. Bradshaw*,‡ IBC Advanced Technologies, Inc., P.O. Box 98, American Fork, Utah 84003, and Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602

This paper summarizes the application of bis(R-chloroamide)s for the preparation of azamacrocyclic ligands. Bis(R-chloroamide)s look like crabs with two reactive claws so the method is called the crablike cyclization reaction. This cyclization strategy has been used to prepare many different types of macrocyclic compounds over the past 10 years including cyclens, cyclams, perazamacrocycles, diazadithiamacrocycles, and some cage compounds. The method is particularly valuable where no other method will work. In general, the crablike cyclization reaction produces the macrocyclic diamides in 40-70% yields. Introduction The macrocyclic polyamines are important complexing agents for the heavy-metal ions.1-3 A great number of methods for their preparation have been used.4-7 Each synthetic method offers some advantages, but each cannot be used in every case because of low reaction yields, availability, the cost of starting materials in the preparation process, and, in many cases, the difficulty of removing protecting groups. Some methods are also limited when other functional groups are present and need to be protected. Thus, it is difficult to point out the perfect method for preparation of the azacrown ethers. This short paper covers the use of bis(R-haloamide)s for the preparation of polyazacrown compounds since the method was discovered in 1988.7 In early papers, the method was described as a “crablike” cyclization because the starting bis(R-chloroamide)s have the appearance of a crab with two reactive claws. We should have used the term KRAB for the first three letters of Krakowiak and first letter of Bradshaw. In the late 1980s, it was discovered that crown ethers attached to silica gel could be used to remove metal ions from aqueous solutions.8-11 At that time, attachment of the crown ether required the synthesis of alkenecontaining macrocycles that could undergo the hydrosilylation reaction with alkoxy-containing silanes to form crown-substituted di- or trialkoxysilanes. This latter material readily reacted with the surface silanol groups of silica gel to form stable Si-O-Si bonds wherein surface silanes contained the covalently bound crown ethers. All oxygen-containing crown ethers are not great complexing agents in water for many metal ions. Thus, there was a need to prepare the azamacrocyclic compounds containing at least one secondary amine function that could be used for attachment to a solid support. The known methods that used protecting groups on nitrogen atoms were not attractive because the protecting group first needed to be introduced in the synthetic * To whom correspondence should be addressed. Phone: (801)378-2415. Fax: (801)378-5474. E-mail: jerald_bradshaw@ byu.edu. † IBC Advanced Technologies, Inc. ‡ Brigham Young University.

pathway and then, after closing the ring, needed to be removed. These additional steps are not welcome when one needs to have a facile and efficient reaction sequence to the final compounds and the lowest overall cost. The crablike method to the polyazacrown ethers uses bis(R-chloroamide) as an intermediate which has two reactive alkyl chloride groups poised and ready to react with a primary amine or a diamine (Scheme 1). The cyclic diamide thus formed is then reduced to the cyclic polyamine. Scheme 1

The advantages of the crablike synthesis of polyazamacrocycles include the following: (1) the process is a straightforward, one-step cyclization from simple and inexpensive starting materials; (2) the secondary amide nitrogen atoms (R′ and/or R′′ ) H) in the crablike bis(R-chloroamide) starting material are unreactive as a nucleophile so nitrogen protecting groups are not needed; (3) the process is short, and the overall process yields for the polyazacrowns are much higher yields than those when protecting groups are employed; (4) the chloride leaving group is activated by the neighboring amide group, but the molecule does not have the blistering properties of a β-chloroamine; (5) the starting bis(Rchloroamide)s are easily prepared from diamines and chloroacetic anhydride or chloroacetyl chloride in quantitative yields. Bis(R-chloroamide) is prepared by treating the diamine with chloroacetic anhydride (or chloroacetyl chloride) followed by evaporation of the solvent. Bis(Rchloroamide) is usually clean and does not require additional purification. The cyclization reaction is carried out by treating bis(R-chloroamide) with a primary amine or secondary diamine in acetonitrile using a

10.1021/ie0004038 CCC: $19.00 © 2000 American Chemical Society Published on Web 08/16/2000

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carbonate base to produce the macrocyclic diamide in good yields. The base could be sodium, potassium, or cesium carbonate or triisobutylamine. The best results were obtained using the carbonates. It is possible that internal hydrogen bonding between the reacting diamine and starting bis(R-chloroamide) provides a pseudotemplate and favors the cyclization process. The first crablike cyclization reaction formed a hydrazine-containing crown ether by treatment of a hydrazine-containing bis(R-chloroamide) with a diamine (Scheme 2).12 This reaction introduced the possibilities

Scheme 4

Scheme 2

chloroamide)s to give two hydroxy-substituted tetraazacrowns in excellent yields (Scheme 5).15,16 An azacrown Scheme 5

of using bis(R-chloroamide)s for the preparation of all types of polyazacrown ethers. Treatment of a primary amine with bis(R-chloroamide) forms a 1:1 cycloadduct wherein the primary amine reacts with the two reactive alkyl chlorides of the starting material (Scheme 3). The Scheme 3

with two hydroxyethyl groups attached to ring nitrogen atoms has also been prepared by the crablike cyclization reaction (Scheme 6).17,18 Again, using a carbonate base Scheme 6

primary amine reactant could have other heteroatoms or groups, such as morpholine, (CH2CH2O)nCH2CH2OH, (CH2)nNEt2, and CH2CH2NHC(O)Me (not shown in Scheme 3), all of which can also coordinate with complexed metal cations. Macrocycles with hydroxy substituents are possible because the amine function is more reactive as a nucleophile using sodium carbonate as the base rather than the nonionized hydroxy group. A pendant amide group as shown in Scheme 3 allows for the preparation of polyaza- or perazacrowns with reactive amine side groups after a reduction step.13 Reaction of the crablike starting material with a bissecondary amine gave a 1:1 cycloadduct where each terminal secondary amine reacted with the alkyl chloride function on the ends of bis(R-chloroamide)s. In one case, a secondary triamine was reacted to give perazacrown with a secondary amine substituent in the side chain (Scheme 4).14 Macrocyclic polyazacrown ethers containing a hydroxy functional group attached to a ring carbon atom can easily be prepared. For example, N,N′-dibenzyl-2-hydroxy-1,3-propanediamine was treated with two bis(R-

ensures that the amine nitrogen atoms react as nucleophiles and not the hydroxy oxygen atoms. The crablike cyclization reaction has been used in a two-step method to prepare polyazacrowns containing one unsubstituted amine function in the macrocyclic ring.16,17 Previous syntheses of monofunctional polyazacrown macrocycles required the use of two types of protecting groups which could be removed sequentially. These types of crowns have been prepared using the Richman-Atkins procedure19-22 to give polyazacrown ethers with one secondary amine in the ring. Barefield and co-workers prepared similar compounds using template cyclizations and benzyl protecting groups.23,24 In all of the previous methods for the preparation of monofunctionalized polyazacrown ethers, many steps were required to obtain compounds similar to those

Ind. Eng. Chem. Res., Vol. 39, No. 10, 2000 3501 Scheme 7

ing beltlike compounds occurred (Scheme 9).25 No 1:1 cyclization product was observed in this reaction. It is interesting that the piperazine units of the 2:2 macrocycle were in the chair form as determined by an X-ray crystal analysis.25 As mentioned above, a major advantage of the crablike cyclization method is that it allows macrocyclic compounds to be formed without protecting the primary nitrogen atoms. Where the diamine reactant is composed of two primary amines, only one primary amine will react with one chloroacetyl group to form the macrocyclic diamide containing two secondary amine functions (Scheme 10).26 The unwanted side reaction,

obtained by the two-step crablike cyclization. The amide nitrogen atoms of the crablike intermediate are not effective nucleophiles so that reaction takes place only through the amine nucleophiles of the reacting diamine (Scheme 7).16-18 This alleviates the need for protecting groups on the amide nitrogen atoms. Reduction of the cyclic diamide results in a polyazacrown ether with one or two secondary amine functions. The crablike cyclization reaction makes possible a one- or two-step, high-yield synthesis of the muchstudied cyclam, [14]N4, compounds. N,N′-Bis(2-hydroxyethyl)-substituted [14]N4 is an example (Scheme 8).17

Scheme 10

Scheme 8

This dihydroxy-substituted cyclam could be used to make cagelike compounds. Rigid starting materials can cause 2:2 and 3:3 cyclizations to take place. When bis(R-chloroamide) prepared from piperazine was treated with piperazine, 2:2 and 3:3 cyclocondensations to form piperazine-contain-

cyclization on one primary amine nitrogen atom, probably does not occur because of the rigidity of the crablike bis(R-chloroamide). Up to now, synthesis of polyazacrown ethers with two secondary amine functions required the two primary amines to be protected with tosyl, benzenesulfonyl, or mesyl groups (RichmanAtkins procedure) and the cyclization reaction was followed by a deprotection step. The crablike cyclization process easily simplifies these multistep processes. For example, Scheme 10 shows the reaction of N,N′-bis(chloroacetyl)ethylenediamine with trans-1,2-diaminocyclohexane in acetonitrile in the presence of sodium carbonate to form 4,9-dioxo-2,5,8,11-tetraazabicyclo[10.4.0]hexadecane.26 Another example is shown in Scheme 11.26 The yield of the ring closure step is usually around 40-50%.

Scheme 9

Scheme 11

The rigidity of N,N′-bis(chloroacetyl)-trans-1,2-diaminocyclohexane allows for an unusual reaction with 2-[(2aminoethyl)amino]ethanol.26,27 The crablike bis(R-chloroamide) reacted with both the primary and secondary amines to close the 12-membered ring (Scheme 12).

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Scheme 12

The above approach to the tetraaza-12-crown-4 ligands is very useful for preparing ligands for MRI imaging with a Gd3+ chelate and for other similar applications. The crablike cyclization method has now reduced the cost for the two most important tetraazamacrocyclic ligands (cyclen and cyclam) that are used for MRI imaging, for treatment of retroviral infection, and for anti-HIV activity. For example, unsubstituted cyclam has recently been prepared in a high yield using this approach (Scheme 13).28 This new synthetic method will Scheme 13

allow for more research in these important medicinal chemistry areas. Because similar polyazamacrocycles are often attached to antibodies for cancer therapy or tumor imaging, other syntheses using the crablike cyclization Scheme 14

process have been developed. In one example, N,N′-bis(dibromoacetyl)-1,2-ethanediamine, which is more reactive than the dichloro derivative, was used in the ring closure step in the synthesis of tetraza-12-crown-4tetraacetic acid containing an aminobenzyl substituent (Scheme 14).29 These authors state, “Construction of the polyazamacrocyclic ring is crucial for successful synthesis of macrocyclic bifunctional chelating agents (BCAs). Previously reported cyclization methodologies for preparing 12-membered polyazamacrocycles include the reaction of deprotonated tosylamides with alkyl ditosylates (Richman-Atkins cyclization) and of diamines with BOC-protected aminodisuccinate esters. Use of these methodologies for BCAS synthesis adds protection and activation steps, making the total procedure longer. The bimolecular cyclization between a bis(R-bromoamide) and a diamine does not require any protection or activation steps in the synthetic approach. This cyclization methodology, which was originally developed by Bradshaw, is simpler and more convenient than previously reported methods and is applicable to the preparation of other pendant functions or ringexpanded congeners with appropriate bis(R-bromoamide)s and polyamines.” An internal crablike cyclization reaction was reported by Bowman-James and co-workers.30 The diethylphosphonamide of 4-tosyldiethylenetriamine was first treated with chloroacetyl chloride followed by deprotection and cyclization in ethanol in the presence of sodium carbonate to form a triaza-9-crown-3 ligand in 68% yield (Scheme 15). Chiral macrocyclic compounds have been prepared by the crablike method.31 Chiral bis(R-chloroamide) derivatives of chiral 1,2-diphenylethylenediamine were obtained by treating the diamine either with chloroacetyl chloride or with chloroacetic anhydride in the presence of a base. The yield was relatively low (50-60%) for this transformation, but chiral macrocyclic diamides were prepared in excellent yields when the resulting chiral bis(R-chloroamide) was treated with the appropriate R,ω-diamines in the presence of a weak base. Reduction of the perazaheteromacrocyclic diamides with lithium aluminum hydride resulted in chiral perazacrown ethers in good yields (Scheme 16).31

Ind. Eng. Chem. Res., Vol. 39, No. 10, 2000 3503 Scheme 15

carbonate in acetonitrile but can also occur in the presence of cesium carbonate (Scheme 18).18 Scheme 18

Scheme 16

An unusual method for the preparation of an anisolecontaining crablike compound was introduced by Bradshaw and co-workers. They used the amidomethylation reaction (Einhorn reaction) to prepare bis(R-chloroamide) in one step from commercially available starting materials in an 87% yield (Scheme 19).33 The N-acylScheme 19

methylenimmonium ions formed from starting N-(hydroxymethyl)-R-chloroacetamide in strong acid are so reactive that they even react with aromatic rings that contain deactivating functional groups. Because of the rigidity of the formed anisole-containing bis(R-chloroamide), cyclization with diamines formed 2:2 as well as 1:1 cyclization products (Scheme 20).33b Cleavage of the Macrocyclic compounds containing sulfur atoms have been prepared using the crablike cyclization method. Only two representative syntheses are shown below. In the first, bis(R-chloroamide) prepared from bis(2-aminoethyl)sulfide was treated with two bis-secondary amines to form two tetraazathiamacrocyclic compounds (Scheme 17).32 The crablike bis(R-chloroamide) intermediates can

Scheme 20

Scheme 17

also react with mercaptan functions as well as with primary or secondary amines to form thiamacrocyclic compounds. An example of this is the synthesis of diazadithia-14-crown-4. The reaction occurred under very mild basic conditions such as those with sodium

methyl moiety of the intraannular methoxy group of the anisole-containing crown macrocycles occurred smoothly to give the intraannular hydroxy-containing crown compounds.33b The nitroanisole-containing crablike compound was also used for preparation of a cryptand in

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62% yield using diaza-18-crown-6 in the presence of sodium carbonate in refluxing acetonitrile (Scheme 21).33 Scheme 21

Bis(R-chloroamide)s can also react with phenols during cyclization.34 This reaction was performed under unusual conditions. A dibenzomacrocyclic compound was prepared using potassium tert-butoxide in dimethylformamide (DMF) instead of a carbonate base (Scheme 22). The same conditions were used for the preparation

of an open-chain bis(benzaldehyde) by treatment of salicylaldehyde with bis(R-chloroamide). The bis(benzaldehyde) was then cyclized with a diamine followed by reduction of the cyclic bis(imine) (Scheme 23). It was found that potassium tert-butoxide gave much better yields in the first step of this synthesis than sodium carbonate.35 Other applications of the crablike cyclization reaction are less known. A bis(chloroacetyl) derivative was obtained in 83% yield from diaza-12-crown-4 and chloroacetic anhydride. Because this compound was not reactive enough in the Menshutskin reaction, even under high-pressure conditions, the chlorine atoms were exchanged for iodine using sodium iodide in acetone. A macrocyclization reaction with N,N′-dimethyldiaza-12crown-4 was performed in acetonitrile under highpressure conditions to give a 73% yield of the desired macrotricyclic salt. The quarternary methyl groups were removed, and the tricyclic diamide was reduced using the diborane-dimethyl sulfide complex (Scheme 24).36 Scheme 24

Scheme 22

Scheme 23

Many macrocycles have been prepared using the Richman-Atkins method during the last 25 years. It has become obvious that, because ligands with more substituents are required, the chemical yields for both cyclization and detosylation using this method have became unworkably low. Riley and co-workers stress that, as substitutions become more complex and sterically congested, the yields decrease and detosylations fail.37-47 For the preparation of more sterically demanding substituents, they used the crablike cyclization

Ind. Eng. Chem. Res., Vol. 39, No. 10, 2000 3505 Scheme 25

method. By taking advantage of the symmetry of the macrocycle, the crablike cyclization method provides a rapid synthesis of the desired polyazamacrocycle. For example, bis(R-chloroamide) of 2,3-diamino-2,3-dimethylbutane underwent cyclization with the tritosylate of diethylenetriamine to give the perazamacrocycle in the remarkably high yield of 72%. Reduction using LiAlH4 gave the saturated, detosylated macrocycle (Scheme 25).38 Scheme 26

Scheme 27

The use of two fused cyclohexane rings as substituents would be expected to confer control over the conformation of a macrocycle. Thus, bis(R-chloroamide) of 1R,2R-diaminocyclohexane was treated with the monoadduct of N-tosylglycine and 1R,2R-diaminocyclohexane in the presence of base in N,N-dimethylacetamide to give the macrocyclic diamide in a 50% yield. The diamide was reduced to the dicyclohexanopentaaza15-crown-5 ligand (Scheme 26).39 More complicated porphyrin-containing molecules were prepared from a tetraaniline derivative of porphyrin via tetrakis(R-chloroamide) (Scheme 27).48,49 In this case, four N-(chloroacetyl) arms were coupled to a tetraazacrown or two triazacrowns. Some general comments concerning the crablike cyclization reaction are in order. The best solvent for the bis(R-chloroamide) cyclization reactions was refluxing acetonitrile. Reactions carried out at low temperatures and for long reaction times gave poor results except for reactions of p-toluenesulfonamides with crablike compounds in DMF or dimethylacetamide. Generally, the reactants were mixed at room temperature, and the solution was immediately heated to reflux temperature.16,18 When high dilution techniques were used, the reactants were slowly added to refluxing acetonitrile. A mixture of acetonitrile and DMF was used in a few cases where one of the reactants was not soluble in pure acetonitrile. Although a complete study of solvent systems has not been done, the yields were better in acetonitrile than in ethanol. The cyclic diamide products of the crablike cyclization reaction were reduced using borane-tetrahydrofuran, borane-dimethyl sulfide, or lithium aluminum hydride. Reduction with borane is straightforward, but some precautions must be taken as described in the relevant papers. The resulting macrocycle-BH3 complex was decomposed by an overnight treatment with 18% aqueous HCl acid at room temperature and then 15 min at reflux temperature. Often, the product was pure after

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extraction from the reaction mixture at pH ) 12. If not pure, the macrocycles were purified on short silica gel columns using methanol-30% aqueous ammonia (5:1 to 10:1) or reverse-phase chromatography. The product after column chromatography often needed to be dissolved in toluene or chloroform and filtered to remove precipitated inorganic material. The yields for crablike cyclizations to prepare 1215-membered rings were 50% or higher. The preparation of the [14]N4 macrocycles shown above is particularly favorable with yields up to 70%. A careful addition of the two reactants under high-dilution conditions using syringe pumps gave the [14]N4 compounds in yields of 80%. Other reaction conditions (reaction times, stirring speed, degree of dilution, base concentration, etc.) were not optimized because of the already high yields for the preparation of the cyclams.17 It is evident that the crablike cyclization reaction is a convenient method to prepare a great variety of azacrown macrocycles in good yields. Some of the polyazaproducts included N-pivot lariat ethers, polyazacrowns and cyclams with one or two unsubstituted ring nitrogen atoms, perazacage compounds, and polyazacrowns containing sulfur atoms. This new method could become the method of choice to prepare the functionalized polyaza- and perazacrown macrocycles. In many cases, the crablike cyclization reaction was the only way to make the desired polyazacrown ether. Acknowledgment The authors thank the Office of Naval Research for financial support. Literature Cited (1) Lindoy, L. F. Heavy Metal Chemistry of Mixed Donor Macrocyclic Ligands: Strategies for Obtaining Metal Ion Recognition. In Synthesis of Macrocycles; Izatt, R. M., Christensen, J. J., Eds.; Wiley-Interscience: New York, 1987; pp 53-92. (2) Hancock, R. D.; Martel, A. E. Ligand Design for Selective Complexation of Metal Ions in Aqueous Solution. Chem. Rev. 1989, 89, 1875. (3) Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R. L. Thermodynamic and Kinetic Data for Macrocycle Interaction with Cations, Anions and Neutral Molecules. Chem. Rev. 1995, 95, 2529. (4) Krakowiak, K. E.; Bradshaw, J. S.; Zamecka-Krakowiak, D. J. Synthesis of Aza-crown Ethers. Chem. Rev. 1989, 89, 929. (5) Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M. Aza-crown Macrocycles; John Wiley & Sons: New York, 1993. (6) Pietraszkiewicz, M. Synthetic Methods in Supramolecular Chemistry. J. Coord. Chem. 1992, 27, 151. (7) Krakowiak, K. E.; Bradshaw, J. S.; Izatt, R. M. Improved Methods for the Synthesis of Aza-Crown Macrocycles and Cryptands. Synlett 1993, 611. (8) Bradshaw, J. S.; Bruening, R. L.; Krakowiak, K. E.; Tarbet, B. J.; Bruening, M. L.; Izatt, R. M.; Christensen, J. J. Preparation of Silica Gel-Bound Crown Ethers and Their Cation Binding Properties. J. Chem. Soc., Chem. Commun. 1988, 812. (9) Izatt, R. M.; Bruening, R. L.; Bruening, M. L.; Tarbet, B. J.; Krakowiak, K. E.; Bradshaw, J. S.; Christensen, J. J. Removal and Separation of Certain Metal Ions from Aqueous Solutions Using a Silica Gel-Bonded Macrocycle. Anal. Chem. 1988, 60, 1825. (10) Bradshaw, J. S.; Krakowiak, K. E.; Tarbet, B. J.; Bruening, R. L.; Biernat, J. F.; Bochenska, M.; Izatt, R. M.; Christensen, J. J. Silica Gel-Bound Aza-Crowns for Selective Removal and Concentration of Metal Ions. Pure Appl. Chem. 1989, 61, 1619. (11) Bradshaw, J. S.; Izatt, R. M. Crown Ethers: The Search for Selective Ion Ligating Agents. Acc. Chem. Res. 1997, 30, 338. (12) Bradshaw, J. S.; Krakowiak, K. E.; Wu, G.; Izatt, R. M. Convenient Synthesis of Crown Ethers Containing a Hydrazine Moiety. Tetrahedron Lett. 1988, 29, 5589.

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Received for review April 11, 2000 Revised manuscript received June 5, 2000 Accepted June 13, 2000 IE0004038