EP0181926A1 - Cubanes substitues - Google Patents

Cubanes substitues

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Publication number
EP0181926A1
EP0181926A1 EP85902863A EP85902863A EP0181926A1 EP 0181926 A1 EP0181926 A1 EP 0181926A1 EP 85902863 A EP85902863 A EP 85902863A EP 85902863 A EP85902863 A EP 85902863A EP 0181926 A1 EP0181926 A1 EP 0181926A1
Authority
EP
European Patent Office
Prior art keywords
cubane
metal
activator
stabilizer
moiety
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP85902863A
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German (de)
English (en)
Inventor
Philip E. Eaton
Graziano Castaldi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University Patents Inc
Original Assignee
University Patents Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Patents Inc filed Critical University Patents Inc
Publication of EP0181926A1 publication Critical patent/EP0181926A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/10—Mercury compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/90—Ring systems containing bridged rings containing more than four rings

Definitions

  • This invention pertains to novel substituted cubanes and to a novel process for the direct substitution of desired substituents onto the cubane nucleus.
  • a number of cubane mono- and dicarboxylic acid derivatives have been examined for their medical properties. See U.S. Patents 3,517,055 and 3,551,576 [1-aminomethylcubane-4-carboxylic acid having anti-fibrinolytic properties]; U.S. Patents 3,418,368, 3,538,160 and 3,562,317 [1-amino- and 1-aminomethyl- cubane and mono- and dialkylamino derivatives thereof, useful as antiviral agents]; U.S. Patent 3,558,704 [1-amino- and 1-aminoalkyl- 4-methylcubanes and mono- and dialkylamino derivatives thereof, useful as antiviral agents].
  • polysubstituted cubanes can conveniently and easily be generated from cubanes having at least one appropriate activator/stabilizer moiety, which activator/stabilizer moiety facilitates deprotonation of carbons on the cubane nucleus beta to said moiety upon exposure of the cubane to a strong base; said moiety may then stabilize the resulting anion together with its counter-ion.
  • the counter-ion is a metal or, metal derivative more or less ionically or covalently bound to the anion. All such cubane derivatives are called cubylmetallics. Exchange of one counter-ion for another of a different metal or metalloid permits the preparation of the full range of these cubylmetallics. Reactions of these cubylmetallics with various electrophilic-type reagents makes it possible to systematically generate novel cubanes substituted at any or all of the previously unavailable substitution sites.
  • M 5 +n B 5 -n , and M 6 +n B 6 -n may be the same or different and each represent a strong base independently selected from the group M +n B -n , wherein M +n is a metal ion, B -n is a base, and n is an integer 1-6; M 1 X 1 p , M 2 X 2 p ,
  • M 3 X 3 p, M 4 X 4 p, M 5 X 5 p, and M 6 X 6 P may be the same or different and each represent a metal salt independently selected from the group MX p , wherein M represents a metal or a metal derivative, X represents an anion, and p is an integer 1-6; E is an electrophilic-type reagent; C is M 1 + n , M 1 X 1 p-1, or E 1 '; D is
  • the starting material (compound IV) is suitably a cubane having as a substituent thereon one activator/stabilizer moiety, designated "A".
  • activator/stabilizer moiety is meant a substituent
  • activator/stabilizer moieties suitable for use in this invention are, e.g., those described by Beak, P., and V. Sniekus, Ace. Chem. Res. 15:306(1982), as being directors of ortho-lithiation of aromatic and heterocyclic systems.
  • Preferred activator/stabilizer moieties include substituted or unsubstituted: amino- carbonyls (carboxamides) and their thio- analogs; oxazolines; imides; amines; carbamates; nitriles; esters; aminoalkyls; hydroxyalkyls; sulfonamides; alkylamines; ethers; ketals; acetals; nitros; and other groups possessing an unshared pair or pairs of electrons.
  • Compound IV may also optionally be substituted by a non-activator moiety at position 4, i.e., R may be hydrogen or any non-A radical.
  • the cubane with the activator/stabilizer group in place (IV) is then reacted with a strong base M +n B -n , wherein M +n is a metal ion, B -n is a base, and n is an integer 1-6.
  • suitable bases are alkyl metals, metal hydrides, metal amides, metal alkoxides, metal alkyl amides, metal-bis(trialkylsilyl) amides, or mixtures thereof.
  • t-Butyl lithium, potassium hydride, potassium t-amylate, sodamide, and lithium tetramethylpiperidide are examples from many of suitable choice.
  • the reaction is allowed to proceed at 0-50°C, preferably at about 20-30°C, for about 0.1-10 hours, preferably for as short a time as possible, with stirring.
  • suitable solvents for this reaction are aprotic polar solvents, e.g. tetrahydrofuran, ether, dioxane, tetramethyl- ethylene diamine, or hydrocarbon solvents optionally containing aprotic polar components, e.g. tetramethyl- ethylenediamine:hexane (from about 0:100 to about 50:100 v/v).
  • the counter-ion may be exchanged by reaction with salts of other metals (MX p , wherein M is a metal; X is an anion, simple or complex, of one or more species, or an organic radical; both M and X can each be monoor polyvalent; and p is an integer 1-6), e.g. mercuric chloride, magnesium bromide, manganous chloride, stannic chloride, zinc chloride, cuprous cyanide, palladium chloride, cadmium chloride, aluminum chloride, etc., or their organic derivatives, e.g. phenylmercury chloride, diethylaluminum chloride, cubylmetallic, etc., to yield compounds of Formula VI.
  • MX p salts of other metals
  • The. cubyl portion of the cubylmetallics (V and VI) is highly reactive and can be expected to react readily according to procedures known in the art with electrophilic-type reagents (E) to give compounds of Formula VII.
  • electrophilic-type reagents suitable for use in this invention are, e.g.
  • D 2 O or alcohols-O-D deuterium
  • metal salts metal, metal salt
  • sulfonyl halides sulfone
  • aldehydes and ketones alcohols
  • carbon dioxide carboxylic acid
  • acid chlorides anhydrides, and esters
  • ketones and/or tertiary alcohols formamides
  • carboxaldehyde silyl halides (silanes); borates/hydrogen peroxide (hydroxyl); cyanates (carbamate); alkyl, aryl, and aralkyl agents (alkyl, aryl. Or aralkyl); halides (halide); nitrites or nitrosyl halides (nitroso); disulfides
  • cubylmetallics may be radical reactions.
  • cubylmercurials may react with halogens such as iodine or bromo in this fashion to give the corresponding iodo- or bromocubanes.
  • halogens such as iodine or bromo
  • Such cubylmercurials also will react with sodium borohydride and an electron-deficient alkene in a radical chain reaction resulting in substitution of the alkene onto the cubane nucleus.
  • the products of Formulas V, VI, and VII can be isolated and purified according to methods well known to those skilled in the art, e.g., by extraction and distillation or crystallization.
  • the compounds of Formulas V,VI, or VII can be exposed to strong base as above to generate the compound of Formula VIII, which in turn can be converted to compounds of Formulas IX and/or X.
  • the procedure can be repeated yet again to yield compounds of Formulas XII and/or XIII via compounds of Formula XI from compounds of Formulas VIII, IX, or X.
  • the starting material (compound XIV) is suitably a cubane having two activator moieties A and A', which moieties may be the same or different and which are each independently selected from those activator moieties described as suitable for compound IV above.
  • Compounds of Formula XIV are conveniently derived from compounds of Formula II by methods well known to those skilled in the art. See, e.g., Edwards, Farrel, and Langford, supra.
  • the compounds of Formula XIV are reacted with a strong base (M B ) to yield an intermediate cubylmetallic (XV) which can be reacted with a metal salt (MX p ) to give cubylmetallic (XVI); either (XV) or (XVI) can be reacted with an electrophilic-type reagent (E) to give (XVII).
  • M B strong base
  • MX p metal salt
  • E electrophilic-type reagent
  • the base (M +n B -n ), the metal salt (MX p ), and the electrophilic-type reagent (E) are selected from those described above for Scheme A.
  • the compounds of Formulas XV, XVI, and XVII can be isolated, or can be exposed to base M 2 +n B -n to form compounds of Formula XVIII, which in turn can be converted to compounds of Formulas XIX and/or XX.
  • the procedure can be repeated to yield compounds (XXI) through (XXXII).
  • exposure to base (M +n B -n ), metal salt (MX p ), and electrophilic-type reagent (E) can be manipulated to yield compounds wherein C,D,G,J,Q, and U are the same or different.
  • two* substituted cubanes can be condensed by standard procedures, as in the reaction of an amine-substituted cubane with a carboxylic acid-substituted cubane, to yield a dicubane molecule linked via a standard peptide bond.
  • the direct attachment of one cubane to another may be achieved by reductive coupling of cubylmetallics, according to procedures known in the art. See, e.g., Negishi, supra.
  • the process of the present invention provides great flexibility in achieving the synthesis of any given desired substituted cubane, and also affords the production of the large class of new polysubstituted cubanes represented by compounds V - XXXII and derivatives thereof .
  • Cubane carboxylic acid chloride (1.23g) prepared as described by Edward, Farrel, and Langford, supra, was dissolved in 5 ml dichloromethane. The solution was added slowly under nitrogen to a stirred solution of 2 g diisopropylamine in 5 ml dichloromethane cooled to -10 °C. After the addition was completed the mixture was allowed to warm to room temperature and stirred at that temperature for two hours. Water. (10 ml) was added. The organic layer, was then separated and washed, in order, with 5% aqueous hydrochloric acid, water, and 5% aqueous sodium bicarbonate, then dried over anhydrous sodium sulfate.
  • a solution of lithium tetramethylpiperidide was prepared by adding slowly at room temperature under nitrogen a solution of n-butyllithium (0.22 ml in a 1.6 M solution in hexane, 0.35 mmol) to a stirred solution of tetramethylpiperidine (55 mg, 0.39 mmol) in dry tetrahydrofuran (1.8 ml) and allowing 10 minutes for complete reaction.
  • the solution of the title compound is added (or vice versa) to a solution of an appropriate electrophile such as an aldehyde, ketone, carbonyl compound, alkyl halide, acyl halide, etc. in stoichiometric or excess amounts, the ensuing reaction will produce 2-substituted-1-diisopropylaminocarbonylcubanes in moderate to excellent yields.
  • an appropriate electrophile such as an aldehyde, ketone, carbonyl compound, alkyl halide, acyl halide, etc.
  • a solution of lithium tetramethylpiperididg in tetrahydrofuran was prepared by adding slowly at room temperature under nitrogen a solution of n-butyllithium (1.6 M in hexane, 1.73 mmol, 1.08 ml) to a stirred solution of tetramethylpiperidine (0.269 g, 1.91 mmol) in dry tetrahydrofuran (9 ml). The mixture was stirred for 10 minutes, then anhydrous mercuric chloride (59 mg, 0.217 mmol) was added in one portion, and the mixture stirred for one minute.
  • Cubane 1,4-dicarboxylic acid chloride (0.6g, 2.6 mmol, prepared as described in Cole, T.J., Jr., Ph.D. Thesis, The University of. Chicago (1964); Edward, Farrel, and Langford, supra), was dissolved in 10 ml dichloromethane and the solution was added slowly under nitrogen to a stirred solution of 2 g diisopropylamine in 10 ml dichloromethane previously cooled to -10 °C. After the addition was completed the mixture was allowed to warm to room temperature and stirred at that temperature for 2 hours. Water (2 ml) was added.
  • a solution of lithium tetramethylpiperidide was prepared by adding slowly at room temperature under nitrogen a solution of n-butyllithium (1.08 ml in a 1.6 M solution in hexane, 1.73 mmol) to a stirred solution of tetramethylpiperidine (0.269 g, 1.90 mmol) in dry tetrahydrofuran (9 ml) and allowing 10 minutes for competion of the reaction.
  • the solution of the title compound is added to (or vice versa) a solution of an appropriate electrophile such as an aldehyde, ketone, carbonyl compound, alkyl halide, acyl halide, etc., in stoichiometric or excess amounts, the ensuing reaction will produce 2,7-disubstituted-1,4-bis (diisopropylaminocarbonyl) cubanes in moderate to excellent yields.
  • an appropriate electrophile such as an aldehyde, ketone, carbonyl compound, alkyl halide, acyl halide, etc.
  • a solution of lithium tetramethylpiperidide in tetrahydrofuran was prepared by adding slowly at room temperature under nitrogen a solution of n-butyllithium (1.6 M in hexane, 2.5 mmol, 1.56 ml) to a stirred solution of tetramethylpiperidine (0.385 g, 2.73 mmol) in dry tetrahydrofuran (10 ml). The mixture was stirred for 10 minutes, then anhydrous mercuric chloride (85 mg, 0.31 mmol) was added in one portion, and the mixture stirred for one minute.
  • 1,4-Bis(diisopropylaminocarbonyl) cubane (47 mg, 0.131 mmol, prepared as in Example V), was added in one portion with stirring and the reaction mixture was stirred at room temperature for five minutes. Water (10 ml) was added and the mixture was washed, in order, with aqueous cupric sulfate, water, and brine, then dried over anhydrous sodium sulfate. Evaporation of the solvent under, vacuum left the crude cubylmercury derivatives in which each cubane residue is bound to one or more mercury atoms and each mercury atom to either one or two cubane residues, as shown by mass spectroscopy and nuclear magnetic resonance analysis.
  • This ketone is clearly the product of condensation between the cubyllithium derived from the diethylaminocarbonylcubane with the electrophilic function of another molecule of diethylaminocarbonylcubane .
  • novel lithium tetramethylpiperidine/ HgCl- system of this invention is generally applicable as a means of inducing ortho-substitution on other compounds with s character in their C-H bonds similar to that found in cubane.
  • diethylbenzamide, ethyl benzoate and benzonitrile are ortho-mercurated rapidly on treatment with the mixture.
  • the diisopropylamide of 1-methyl- cyclopropanecarboxylic acid has also been mercurated using this system.
  • the corresponding, cyclobutane is inert, an observation appropriate to the significantly lower s character in cyclobutane C-H bonds.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Substances cubylmétalliques et leurs dérivés, ainsi que leurs procédés de production.
EP85902863A 1984-05-23 1985-05-23 Cubanes substitues Withdrawn EP0181926A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US61370884A 1984-05-23 1984-05-23
US613708 1984-05-23

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EP0181926A1 true EP0181926A1 (fr) 1986-05-28

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WO (1) WO1985005357A1 (fr)

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WO2022133111A1 (fr) * 2020-12-16 2022-06-23 Regents Of The University Of Minnesota Composés cubanyle biguanide

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US3259543A (en) * 1961-10-31 1966-07-05 Allied Chem Pesticidal ketone adducts
US3296288A (en) * 1963-04-29 1967-01-03 Ethyl Corp Organomercury group vb metal carbonyls
US3542868A (en) * 1965-03-24 1970-11-24 Smithkline Corp Pentacyclononaneamines
FR5107M (fr) * 1965-03-24 1967-05-22
US3418368A (en) * 1965-03-24 1968-12-24 Smith Kline French Lab Pentacyclo[6.2.0.02,6.03,10.05,9] decaneamines
US3538160A (en) * 1965-03-24 1970-11-03 Smithkline Corp Pentacyclooctaneamines
US3449422A (en) * 1966-02-09 1969-06-10 Smithkline Corp Pentacycloundecane amines
US3476788A (en) * 1966-09-19 1969-11-04 Mobil Oil Corp Derivatives of the growth reaction of ethylene with trihydrodicyclopentadienyl aluminum
US3780108A (en) * 1966-10-04 1973-12-18 Smithkline Corp Caged ketone
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US3558694A (en) * 1966-12-23 1971-01-26 Allied Chem Pesticidally active keto acid substituted chlorinated polycyclic ketone c10cl10o
US3558704A (en) * 1967-10-04 1971-01-26 Du Pont 4-methylcubaneamines
US3597487A (en) * 1969-02-25 1971-08-03 Ethyl Corp Chain growth of organo-magnesium compounds
US3551576A (en) * 1969-07-28 1970-12-29 Merck & Co Inc Anti-fibrinolytic agent
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