SUBSTITUTED CUBANES

Abstract: Cubylmetallics and derivatives thereof, and methods for making same.

Description: Substituted Cubanes This invention pertains' ' to novel substituted cubanes and to a novel process for the direct substi¬ tution of desired substituents onto the cubane nucle¬ us. Cubane, having the structure of Formula T was first synthesized by- Eaton- and Cole- at the univer¬ sity of Chicago in 1964. Since then a number of modifications have been made; at present the preferred synthesis is preparation of a Diels-Alder dimer of a bromocyclopentadienone derivative, followed by photo- closure to a cage compound and Favorskii contraction to the cubane—1,4-dicarhoxylie; acid αf Formula II: See Eaton, P.E. and T.W. Cole, Jr., J. Am. Chem. Soc. 86:962,3157(1964); Chapman, N.B., J.M. Key, and K.J. Tόyne, J. Org. Chem. 35:3860(1970); Luh " , . T.-Y. and L.M. Stock, J. Org. Chem. 37:338(1972); Klunder, A.J.H. and B. Zwanenburg, Tetrahedron 4131 (1972) . The unsubstituted compound is then derived from the diacid. See Eaton and Cole, supra; Barborak, J.C., L. Watts, and R. Pettit, J. Am. Chem. Soc. 88:1328(1966). Cubanes possess a variety of unique properties. They are the most highly strained organic compounds available in quantity. --The strain energy of cubane is approximately 166 kcal/mole, one of the highest known. The density of cubane is extraordinarily high, 1.29 g/cc. These properties render cubanes interesting as potential explosives. In addition, since a variety of " caged compounds, particularly adamantane, have been found to be useful in medicine, cubanes are also interesting as biological and medical agents. 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 [l-aminomethylcubane-4-carbox lic acid having an- ti-fibrinolytic properties]; U.S. Patents 3,418,368, 3,538,160 and 3,562,317 [1-amino- and 1-aminometh l- cub ' ane and mono- and dialkylamino derivatives thereof, useful as ' antiviral agents]; ϋ.S " . Patent 3,558,704 ri-amino- and 1-aminoalkyl- 4-methylcubanes and mono- and dialkylamino " derivatives thereof, usefui " as antiviral " agents] . These compounds are all derived by straightforward ' standard organic chemistry steps from the mono- or dicarboxylic acid of cubane. See also Edward, J.P. , P.G. Farrel, and G.E. Langford, J. Am. Chem. Soc. 98:3075 - (1976)-. However, further ex¬ amination of substituted cubanes has been halted by the unavailability of reactive derivatives other than the mono- and 1,4-dicarboxy-lic acids and their deriva¬ tives. Since 1964, numerous attempts have been made to synthesize derivatives of cubane with substitutions at other than the 1- and/or 4-positions. To date, all successful attempts have proceeded by ring closure of intermediates having the desired substituents already in place. Barborak, Watts, and Pettit, supra, and Eaton, P.E. and T.W. Cole, Jr., Chem. Comm. 1493(1970) have provided independent syntheses of the 1,3-diacid, but neither of these can be " scaled up " -realistically: in the first, the ' cost of starting with ' cyclobutadiene iron tricarbonyl is- completely prohibitive; • in the second, there is an insurmountable solubility problem with one of the- key intermediates. Slobodin, Y.M; , I.V. Aleksandrov, and A.P. Khitrov, Zh. Org. Khi . 13:1377(1977) have reported the low-yield phototetra- merization of diphenylacetylene to octaphenylcubane. Pelosi, L.F. and W.T. Miller, ' J. Am. Chem. Soc. 98:4311(1976) have reported the synthesis of octa- (trifluoromethyl)cubane via photoisomerization of the dimers ' of tetra(trifluoromethyl)cyclobutadiene. Unfortunately, the reactivity of the unactivated trifluoromethyl groups in this compound is so limited that there is little value in using this compound in further synthetic schemes. Incorporation of subs- tituents onto the cubane via ring closure from the substituted intermediate is severely hampered by the conditions required for closure. There is therefore a need for a process which provides direct substitution on the cubane nucleus. Any scheme for the direct functionalization of cubane depends on the unique nature of the cubane skeleton. The highly strained structure precludes use of brute force methods. There is a need for a controlled functionalization which proceeds via cubyl intermedi¬ ates that can be formed and utilized under mild conditions in well-defined steps. It has now been discovered that polysubstituted cubanes can conveniently and easily be generated from cubanes having at least one appropriate activa¬ tor/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 4 stabilize the resulting anion together with its counter-ion. ' • ' The countersion 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 electro- philic-type reagents makes it possible to systemat¬ ically generate novel cubanes substituted at any or all of the previously unavailable substitution sites. The process will be described in further detail with reference to Schemes A and B, wherein A and 1 are activator/stabilizer moieties; R i& hydrogen or any non-A _ rad,i.cal,; M ..,+n_B.—n, M., 2 +n_B 2 —n, M,,-+n_B_—n, K.,.+n_B.—n, M g n B ~ n , and M β ^ g "11 may be the same or different and each- represent- a, strong base independently select¬ ed from the group M B , wherein M is a metal ion, B~ is a base, and is an integer 1-6; M X , M X , M 3 X 3 p, M 4 X 4 p r M 5 X 5 p, and M 6 X 6 P may be the same or different and each represent a etaL salt indepen¬ dently selected from the group MX , wherein M repre¬ sents a metal or a metal derivative, X represents an anion, and p is an integer 1-6; E is an electro- philic-type reagent; C is M.. n , M X __*,. or E 1 * ; D is M 2 +n , M 2 X 2 χ , or E 2 '; G is 3 +n , M 3 X 3 χf or E 3 *; J is M 4 , ΆV 4 L , or E 4 « ; Q is ^ π , M D X D p _ lf or E ζ ' ; and in all of the above, M, X, and B can be mono- or polyvalent. In Scheme A the starting material (compound IV) is suitably a cubane having as a substituent thereon one activator/stabilizer moiety, designated "A". By "activator/stabilizer moiety" is meant a substituent Compound V, VI, or VII Compound VIII, IX, or X SCHEME A (continued) Compound VIII, IX, or X +n -n _ which facilitates deprotonation and formation of a metal derivative at one or more methine carbons on the cubane nucleus beta to said moiety. Examples of 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 hetero- cyclic systems. Preferred activator/stabilizer moieties include substituted or unsubstituted: amino- carbonyls (carboxamides) and their thio- analogs; oxazolines; imides; amines; carbamates; nitriles; esters; aminoalkyls; hydroxyalk ls; sulfonamides; alkylamines; ethers; ketals; acetals; nitros; and other groups possessing an unshared pair or pairs of electrons. Compound IV may also optionally be sub¬ stituted by a non-activator moiety at position 4, i.e., R may be- hydrogen or- any non-A radical. (See Scheme B for R=A.) Starting materials of Formula IV are known (see, e.g., U.S. Patents 3,517,055, 3,551,576, 3,418,368, 3,538,160, 3,562,317, and 3,558,704, supra) , or are easily prepared from the onocarboxylic. acid ...of Formula III., or from, the di¬ carboxylic acid of Formula II above according to standard synthesis procedures well known to those skilled in the art. See, e.g., Edwards, Farrel, and Langford, supra. The cubane with the activator/stabilizer group in place (IV) is then reacted with a strong base M B " , wherein M is a metal ion, B is a base, and n is an integer 1-6. Examples of suitable bases* are alkyl metals, metal hydrides, metal amides, metal alkoxides, metal alkyl amides, metal-bis(trialkyl- silyl)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. Examples of suitable sol¬ vents 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) . Reaction with the strong base generates an anion beta to the activator/stabilizer " moiety, which anion is necessarily more or less ionically or covalently bound to its counter-ion, M- n from the base M.. n B..~ n to form a cubylmetallic (Formula V) . The counter-ion: may be exchanged by reaction with salts of other metals (MX , wherein M is a metal; X is an anion, simple- o -complex, • of one' or more species-, or an organic radical; both M and X can each be mono- or 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 -ehle-ride*, aluminum chlor¬ ide, etc., or their organic derivatives, e.g. phenyl- mercury chloride, diethylaluminum chloride, cubyl¬ metallic, etc., to yield compounds of Formula VI. 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. Examples of electrophilic-type reagents suitable for use in this invention are, e.g. (the group introduced, E' , is given parenthetically) : D_0 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 (hydrox- yl) ; •cyanates (carbamate) ; alkyl, aryl, and aralkyl agents (alkyl, aryl. Or aralkyl); alides (halide) ; nitrites or nitrosyl halides (nitroso) ; disulfides (sulfides) ; azides/borohydride (amine) ; N-fluoro-N- sulfonamides (fluoro) ; methoxyamine/ ethyllithium (amine) ; boron trichloride (boron halides/borates) ' ; nitric acid (nitro, diazonium) ; 0-(diphenylphosphin- yl)hydroxylamines (primary, secondary, or tertiary amine) ; phosphorus and phosphoryl halides (phosphorus derivatives) ; dinitrogen tetroxide (nitro) ; etc. For a comprehensive review of the use of organometallics in organic syntheses, see Negishi, E., Organometallics in Organic Synthesis (Wiley-Interscience, New York, 1980) . Some of the reactions of cubylmetallics may be radical reactions. Thus, for example, cubylmercurials may react- with- halogens" such"" as iodine- or' bromo in this fashion to give the corresponding iodo- or bromocubanes. 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; See, e.g., Giese, B. and J. Meister, Chem. Ber. 110:2588(1977) . 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. Alternatively, 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. In a similar manner, 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. Selective sequential exposure to base (M +n B " ~ n ) , metal salt (MX_) , and electrophilic-type reagent (E) generates compounds* of Formulas V-XIII wherein C,D, and G are independently determined and may be the same or different. If compound V or VI is allowed to accumulate in a reaction medium containing both a strong base (M n B~ ) -and an electrophilic-type reagent (E) , compounds VII, X, and XIII, wherein E.. ' , E-', and E_ ' are all the same (=E') will spontaneously accumulate. However, this alternative process is only feasible with electrophic-type reagents which are compatible with the strong base and do not inactivate it. In Scheme B, 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., Ed¬ wards, Farrel, and Langford, supra. As in Scheme A^- h -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 ) to give cubylmetallic (XVI) ; either (XV) or (XVI) can be reacted with an electro¬ philic-type reagent (E) to give (XVII) . The base (M +n B "n ) , the metal salt (MX ) , and the electro¬ philic-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~ to form compounds of Formula XVIII, which in turn can be converted to compounds of Formulas XIX and/or XX. In a similar manner, the procedure can be repeated to yield compounds (XXI) through (XXXII) . As in Scheme A, exposure to base 1 1 (M B " ) , metal salt (MX ) , and electrophilic-type .reagent (E) can be manipulated to yield compounds wherein C,D,G,J,Q, and U are the same or different. Also as in Scheme A, compounds of Formulas XVII, XX, XXIII, XXVI, XXIX, and XXXII, wherein E.. ' , E 2 ' , E 3 ' , E. * , E * and E g ' - are all the same (=E') will spontane¬ ously accumulate in a reaction medium containing a strong base and a compatible electrophilic-type reagent. The novel cubylmetallics V, VI, VIII, IX, X (wherein C=M 1 +n or MV ..) , XI, XII, XIII (wherein C=M- +n or M 1 X 1 Λ or D=M_ +n or M 2 X 2 ,), XV, XVI, 1 P~l 2 p-1 XVIII, XIX, XX (wherein C= 1 +n or M 1 X 1 _ ) , XXI XXII, XXIII (wherein C^M * 11 or M 1 X 1 χ or D=**M 2 +?1 o M 2 X 2 ,), XXIV, XXV, XXVI (wherein C=M 1 +n or M 1 X 1 1 p—l . i P~i or D=M-, +n or M 2 X 2 or G=M +n or M 3 X 3 , XXVII, ■ XXVIII, XXIX (wherein C=M 1 +n or MV . χ or D=M 2 +n or 2 2 +r_ "*. ^ +n 4 4 M X 1 or G=M. or M X _ 1 or J=M 4 or M X • _ χ ) , XXX, XXXI, or XXXII (wherein or M 1 X 1 p • - ••• -1. or.-. or M 2 X 2 p-,1 or or M 3 X 3 p-1- or or 4 4 +rι • *. •■ _ M X -, or Q=M-. or M X ,) are the key reactive sr i- . . -^ £τ ~ -** compounds In this process which allow direct function¬ alization of the cubane nucleus and provide access to the heretofore unavailable compounds of Formulas VII, X (C=E 1 *), XIII (C=E 1 ', D=E 2 '), XVII, XX (C=E 1 '), XXIII (C***^', D=E 2 f ), XXVI (C=E 1 ', D=E 2 ' , G=E 3 ' ) , XXIX (C*=E 1 ', D=E 2 ', G=E 3 ', J=E 4 '), and XXXII (C=E ] , ' , D=E 2 ' , G=E 3 ', J=E 4 ', Q=E 5 '). These- compounds are suitable for use in a variety of further reaction schemes, wherein are converted to other substituents according to procedures well known in the art. 12 Compound XV, XVI, or XVII Compound XVIII, XIX, or XX SCHEME B (continued) Compound XVIII, XIX, or XX Compound XXI, XXII, or XXIII Compound XXIV, XXV, or XXVI I SCHEME B (continued) Compound XXIV, XXV, or XXV! Compound XXVII, XXVIII, or XXIX Q=M 5 +n , M 5 X 5 _, or E e ' -" p—1 J U=M 6 + n, uH 6 ^_ lt or E6 . Furthermore, one or more of the moieties A, A' , R, C, D, G, J, Q, or U on compounds V - XXXII may be con¬ verted by well-known standard organic synthesis procedures into yet another activator/stabilizer moiety A" , and the resulting compound can then be used to generate anions beta to A" on the cubane moiety. Further still, it is possible for cubylmetallics of Formulas V, VI, VIII, IX, X (wherein C=M 1 +n or M 1 X 1 ,) , XI, -XII, XIII (wherein C=M T +n or M 1 X 1 , or or M 2 X 2 p-,1) , XV, XVI, XVIII, XIX, XX (wherein or M 1 X 1 p-1,), XXI XXII, XXIII (wherein or M 1 X 1 , or D=M 2 +n or M 2 X 2 , ) , XXIV, XXV, XXVI (where- in or M 1 X 1 p-1, or or M 2 X 2 p-1- or or M 3 X 3 ,), XXVII, XXVIII, XXIX (wherein C*-=M., +n or MVp-.1 or or M 2 ,X 2 p-.1 or or M 3 X 3 p-,1 or +n 4 4 J=M 4 or M X* ) , XXX , XXXI , - or XXXII (wherein C=M n 1 +n or VL 1" 1 p- -1 or D=M 2 +n or M 2 X 2 p- .1 or G=M_ 3 +n or ■ . ". +n 4 4 +n •*. X , or J=M. or M X . or Q=M C or M X - ) to p-1 4 P—l 5 P~l react or condense with an electrophilic group on a compound of Formula VII, VIII (C=E 1 *), IX (C=E 1 I ), X, XI (C^E.^ or D=E 2 r ), XII (C=E 1 ' or D=E 2 '), XIII, XVII, XVIII (C=E 1 *), XIX (C=E 1 '), XX, XXI (C***-^' or D=E 2 ') , XXII (C=E 1 ' or D=E 2 '), XXIII, XXIV (C=E 1 ' or D=E 2 ' or G=E 3 '), XXV (C=E 1 I or D=E 2 ' or G=E 3 ') , XXVI, XXVII (C=E 1 ' or D=E 2 ' or G=E 3 ' or J=E 4 r ) , XXVII (C=E 1 ', or D=E 2 f or G=E 3 ' or J=E 4 '), XXVIII (C^' or D=E 2 ' or G=E 3 ' or J=E 4 '), XXIX, XXX (C=E 1 ' or D=E 2 ' or G=E 3 ' or J=E 4 ' or Q=E 5 ') f XXXI (C=E 1 ' or D=E 2 ' or G=E 3 » or J=E 4 * or Q=E '), or XXXII to yield a bridged dicubane. 16 " "'" This process can be repeated to yield cubane "poly¬ mers".* Likewise, 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. Furthermore, if n=2-6 in the substituent M or * p=2-6 in MX _. , it is possible for said substituent to act as a counter-ion for more than one cubyl anion simultaneously, forming complexes of the formula (cubyl) n X +n or (cubyl) n MX ^ _ All of the procedures given above can also obviously be performed using cubane-l,3-dicarboxylic acid (obtained by the procedure of Barborak, Watts, and Pettit, supra, or Eaton and Cole, Chem. Comm. 1493 (1970) as the starting material in lieu of compound II, to obtain the corresponding analogous cubyl¬ metallics and derivatives thereof. 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 deriva¬ tives thereof. A further understanding of this invention can be had from the following non-limiting examples. As used hereinabove and below unless expressly stated to the contrary, all temperatures and temperature ranges refer to the centigrade system and the terms ambient or room temperature refer to about 20 β C. The term percent or (%) refers to weight percent and the terms mole and moles refer to gram moles. : _ Example I DIISOPROPYLAMINOCARBONYLCUBANE . 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. Evaporation of the solvent and crystallization of the residue from hexane* gave* diisopropylaminocarbonylcubane in 85 % yield. The product was characterized by mass spectro- photo etry, infrared spectra and nuclear magnetic resonance analysis. Example II -. - . l-DIISOPROPYLAMINOCARBONYL-2-LITHIOCUBANE 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. A solution of diiso- propylaminocarbonylcubane prepared as in Example I (10 mg, 0.0432 mmol) in dry tetrahydrofuran (1 ml) was added and the mixture was stirred for 5 minutes to produce a solution containing 1-diisopropylamino- carbonyl-2-lithiocubane. This was demonstrated by quenching the mixture with excess methanol-O-d. Isolation and mass spectroscopic analysis of recovered diisopropylamino- carbonylcubane showed it to be substantially monodeu- terated. - If, instead of quenching with methanol-O-d, 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-substi- tuted-1-diisopropylaminocarboήylcubanes in moderate to excellent yields. Example III MERCURY DERIVATIVES OF DIISOFROPYL_MI15TOCARBOHYLCϋBANE A solution- of lith-ium- • tetramethylpiperididg in" tetrahydrofuran was prepared by adding slowly at room temperature under nitrogen a solution of n-butyl- lithium (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. A solution of diisopropyla inocarbonylcubane (50 mg, 0.216 mmol) in dry tetrahydrofuran (1 ml) was added with stirring and the whole stirred at room temperature for five min¬ utes. Water (10 ml) was added and the mixture was extracted thoroughly with chloroform. The chloroform extract 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 to either one or two 19 cubane residues, as shown by mass, spectroscopy and nuclear magnetic resonance analysis. Example IV IODO- AND BROMO-DERIVATIVES OF DIISOPROPYLAMINOCARBONYLCUBANE The mixture of cubylmercury derivatives described in Example III was dissolved in 7 ml chloroform. Iodine (0.2 g) was added and the reaction mixture stirred 48 hours at room temperature. The reaction mixture was then washed, in sequence, with an aqueous solution of sodium thiosulfate to remove excess iodine, then water, then brine, and dried over sodium sulfate. The solvent was removed * under reduced pressure. The residue was chromatographed on silica gel (4 g)- using hexane- as eluent. The major product was 2-iodo-l-diisopropylaminocarbσnylcubane. The minor product was 2,6-diiodo-l-diisopropylaminocar- bonylcubane. Nuclear magnetic resonance spectroscopic analysis of the remaining material indicated the presence- f..higher iodina.te.d-cubanes... The analogous procedure substituting bromine for iodine gave the corresponding bromocubanes. Example V 1,4-BIS(DIISOPROPYLAMINOCARBONYL)CUBANE 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 diiso- propylamine in 10 ml dichloromethane previously cooled to -10 °C. After the addition was completed the 20 mixture was allowed to warm to room temperature and stirred at that temperature for 2 hours. Water (2 ml) was added. The organic phase was separated, and washed, in order, with 5% aqueous hydrochloric acid, water and 5 % aqueous sodium bicarbonate solution, then dried over anhydrous sodium sulfate. Evaporation of the solvent left 1,4-bis(diisopropylaminocarbonyl)- cubane as a crude solid. ' Crystallization from diethyl ether hexane gave pure material (0.839 g, 90% yield), mp 243-245- °C. Example VI 1,4-BIS(DIISOPROPYLAMINOCARBONYL)-2,7-DILITHIOCUBANE A solution o-f- lithium tetramethylpiperidide was prepared by adding slowly at room temperature under nitrogen a--solutio •-of- n-buty1li hiu • (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. A solution of 1,4-bis- {diisopropy-laminoca-rbonyl).cubane- (50 -mg,-0**.1-4*0- -mmol> prepared as in Example V) in dry tetrahydrofuran (1 ml) was added and the mixture stirred for 5 minutes producing a solution containing both 1,4-bis (diisopro¬ pylaminocarbonyl)-2-lithiocubane and 1,4-bis(diiso¬ propylaminocarbonyl)-2,7-dilithiocubane. This was demonstrated by quenching the mixture with excess methanόl-O-d. Isolation and mass spectroscopic analysis of recovered 1,4-bis(diisopropylaminocarbon¬ yl)cubane showed it to contain up to two deuterium atoms per molecule. If, instead of quenching with methanol-O-d, 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 21 amounts, the ensuing reaction will produce 2,7-disubs- tituted-l,4-bis (diisopropylaminocarbonyl)cubanes in moderate, to excellent yields. Example VII MERCURY DERIVATIVES OF ■ ' _ - " - 1,7-BIS(DIISOPROPYLAMINOCARBONYL)CUBANE -iv A solution of lithium tetramethylpiperidide in tetrahydrofuran was prepared by adding slowly at room temperature under nitrogen a solution of n-butyllithi- um (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 ■ ; • - l,-4—Bis"(di¬ isopropylaminocarbonyl)cubane (47 mg, 0.131 mmol, pre¬ pared 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. Example VIII IODO- AND BROMO- DERIVATIVES OF 1,4-BIS(DIISOPROPYLAMINOCARBONYL)CUBANE The mixture of cubylmercury derivatives described in Example VII was dissolved in 10 ml chloroform. 22 Iodine (0.4 g) was added and the mixture stirred 48 hours - at room temperature. It was then washed, in- order, with an aqueous solution of sodium thiosulfate to remove excess iodine, then water, then brine, and dried over sodium sulfate. The solvent was removed under reduced pressure. The _ residue was chroma- tographed on silica gel (4_g) using hexane as eluent. The major product was 2,7-diiodo-l,4-bis(diisopropyl¬ aminocarbonyl)cubane. The minor product was 2,3,7- triiodo-1,4-bis (diisopropylaminocarbonyl)cubane. Nuclear magnetic" resonance spectroscopic analysis of the remaining material indicated the presence of higher iodinated cubanes. The analogous procedure substituting bromine for iodine gave the corresponding bro ocubanes. Example IX - If cubane itself is used in place of the amido- cubane in. Example II or VI, there is no significant substitution* ( - 2%-)-- of -D * for- H- under- equivalent—or' even far -more drastic conditions. This demonstrates that the presence of an activator/stabilizer group is necessary for efficient deprotonation. To the best of our knowledge, this invention constitutes the first evidence that amide activation as a means of inducing ortho-metallation can be extended beyond aromatic or vinyl systems. 23 Example X XXXIII Lithium tetramethylpiperldide (LiTMP) in tetra¬ hydrofuran (THF) reacted rapidly with diethylamino- carbonylcubane to give, in part, the dicubyl ketone of Formula XXXIII. This ketone is clearly the product of condensation between the cubyllithium derived from the diethylaminocarbonylcubane with the electrophilic function of another molecule of diethylaminocarbonyl¬ cubane. Example XI The 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. Experiments have been done to show that 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. However,, the corresponding, cyclo- butane is inert, an observation appropriate to the significantly lower s character in cyclobutane C-H bonds.

Claims: 24 WE CLAIM: 1. A compound selected from the group consisting of -those of ' the formula: wherein A and A' each Independently represent an activator/stabilizer group, R represents hydrogen or a non—A moiety, and C, D, G, J, Q, and U each independently represent hydrogen, a metal cation, a metal salt cation, or an electrophilic moiety, with the proviso that R, C, D, G, J, Q, and U cannot simultaneously be hydrogen, and derivatives thereof. 2. The compound of Claim 1 wherein C, D, G, J, Q, and U are each independently selected from the group consisting of metals; ' metal salts; deuterium; sulfone; primary, secondary, or tertiary alcohol; acid; ester; ketone; aldehyde; nitrile; silane; hydroxyl; carbamate; alkyl, aryl, or aralkyl group; halide; nitroso; nitrite; nitro group; primary, secondary, or tertiary amine; phosphate; borate; fluoro; boron halides; diazonium; and derivatives thereof. 25 3. A process for making a compound of Claim 1, said process comprising reacting a cubane having as a substituent one or more activator/stabilizer moieties, with a strong base to deprotonate one or more carbons on the cubane nucleus beta to said activator/stabil¬ izer moiety or moieties, isolating the resulting cubylmetallic, and if desired converting said cubyl¬ metallic to a desired derivative by standard proce¬ dures. 4. The process of Claim 3, wherein said activa¬ tor/stabilizer moiety is a substituted or unsubstitut¬ ed: aminocafbonyl or a thio analog thereof.; oxazoline; imide; amine; carbamate; nitrile; ester; aminoalkyl; hydroxyalkyl; sulfonamide; alkylamine; ether; ketal; or acetal. 5. The process of Claim 3, wherein said base is an alkyl metal, metal hydride, metal amide, metal alkoxide, metal alkyl amide, metal-bis (trialkylsilyl)- amide, or mixtures thereof. 6. The process of Claim 5, wherein said base is lithium tetramethylpiperidide. 7. The process of Claim 6, comprising addition¬ ally the step of reacting the resulting lithium salt with a composition comprising HgCl 2 and lithium tetramethylpiperidide to obtain the mercuric or mercuric chloride derivative of cubane. 8. The process of Claim 7, comprising addition¬ ally the step of reacting the resulting mercuric or mercuric chloride derivative of cubane with a halide to obtain corresponding halide derivative of cubane. 26 9. The process of Claim 8 wherein said halide dine. . 10. The process of Claim 8 wherein said halide omine.

Inventors: CASTALDI GRAZIANO, EATON PHILIP E, CASTALDI, GRAZIANO, EATON, PHILIP, E.
Applicants: UNIVERSITY PATENTS INC, UNIVERSITY PATENTS, INC.
Application year: 1985
Main classification: C07C102
IPC codes: C07C233, C07F3