WO1987003278A2 - Synthetic routes to cyclopentanecarboxylic acid derivatives - Google Patents

Abstract

A ring contraction approach is applied to preparation of cyclopentane derivatives, especially 2,2,5,5-tetra-methylcyclopentanecarboxylic acid from cyclohexane compounds. In one aspect, a cyclohexane diazoketone is reacted with an amine (e.g., an alanine ester) to form the corresponding cyclopentane acid amide.

Description

  
 



   SYNTHETIC ROUTES TO CYCLOPENTANECARBOXYLIC ACID
 DERIVATIVES
 Background of the Invention
 This invention relates to the synthesis of intermediates useful in the manufacture of a variety of compounds useful, e.g., as constituents of or intermediates in preparations of fragrances and   fragrant    compounds, flavoring agents and/or   enhances    and especially of synthetic sweetening agents.



   It is well known in the field of synthetic sweeteners that certain branched alkyl   and alkylated    cycloalkylamines, alcohols and carboxylic acids when incorporated into a moiety which is bonded to the amide nitrogen atom, e.g., of   t-aspartamide,    possess unique ability to impart intense sweetness to these molecules. Examples of such amines, alcohols and acids are found, for instance, in U.S. Patent 4,399,163, British Patent 1,434,043, and European Patent 0128654A2. In particular, 2,2,5,5-tetramethylcyclopentanecarboxylic acid is of interest in this connection; see W.D.



  Fuller, M. Goodman and M.S. Verlander, J. Am. Chem. Soc., 107, 5821, 1985.



   Existing methods for preparation of the branched alkyl and alkylated cycloalkyl moieties for these sweeteners are unsatisfactory in many instances and are in need of improvement, e.g., simplification, better yields, milder  conditions, fewer steps, more readily available starting materials, etc.



   Summary of the Invention
 Accordingly, it is an object of this invention to provide such an improved method.



   It is a further object of this invention to provide individual steps useful in a method for preparing the desired branched (cyclo)alkyl moieties wherein these steps are significantly advantageous.



   It is yet another object of this invention to provideprocesses comprising combinations of these steps.



   It is a further object of this invention to provide intermediates useful in the processes of this invention.



   Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.



   These objects have been achieved by providing an overall ring contraction approach to the synthesis of the desired cycloalkyl moieties. This ring contraction involves the conversion of a cyclohexane derivative to a desired cyclopentane derivative. Some of the steps involved in this invention are summarized in the chart below.



   The preferred aspects of this overall synthetic scheme are:
 a process for preparing a diketone of the formula
EMI2.1     
 wherein each of R1, R2, R3 and R4 independently is   H,     
EMI3.1     
  or optionally substituted alkyl, aryl or aralkyl and each of R5 and R6 independently is H, or optionally substituted alkyl, aryl or aralkyl or together   R5    and R6 form a fused ring, comprising
 condensing the corresponding compound of the formula
EMI4.1     
 wherein each of R7 and R8 independently is alkyl,
 in the presence of   Na     or   KO    to form the corresponding cyclic   acyloin,t    and
 then in situ oxidizing the latter product with an effective oxidizing agent to form the diketone;

   and
 a process for preparing a hydra zone of the formula
EMI4.2     
 wherein each of R1, R2, R3 and R4 independently is H, or optionally substituted alkyl, aryl or aralkyl and each of
R5 and R6 independently is H, or optionally substituted alkyl, aryl or aralkyl, or together R5 and R6 form a fused ring, comprising
 reacting the corresponding diketone of the formula  
EMI5.1     
 with hydrazine in the presence of an effective acid catalyst at a pH of 5-11 and, preferably without any special means to remove   H2O;

  ;    and
 a process for preparing a cyclopentanecarboxamide of a primary or secondary amine of the formula
EMI5.2     
 wherein each of R1, R2, R3 and R4 independently is H, or optionally substituted alkyl, aryl or aralkyl and each of
R5 and R6 independently is H, or optionally substituted alkyl, aryl or aralkyl, or together R5 and R6 form a fused ring, comprising
 reacting the corresponding diazoketone of the formula
EMI5.3     
 with the amine;
 and various combinations of these.



   A preferred intermediate for use in these synthetic reactions is the diketone 4, inter alia. It is useful  especially in the preparation of new hydrazone 5.



   In other aspects, this invention also provides a process for preparing a cyclopentane carboxylic acid of the formula
EMI6.1     
 wherein each of R1, R2, R3 and R4 independently is H, or optionally substituted alkyl, aryl or aralkyl and each of
R5 and R6 independently is H, or optionally substituted alkyl, aryl or aralkyl or together R5 and R6 form a fused ring, comprising
 treating the corresponding diazoketone of the formula
EMI6.2     
 under conditions effective to contract the six-membered diazoketone ring to form the five-membered ring of said cyclopentane carboxylic acid
 and a process for preparing a cyclopentane carboxylic acid of the same formula comprising
 reacting the   correscondinq      hvdrazide    of the formula
EMI6.3     
 with an oxidizing agent effective to convert the hydrazo group into an azo group.



   Detailed Discussion
 Much of the following discussion is phrased in terms of preparing   2,2,5, 5-tetramethylcyclopentanecarboxylic    acid   (7) since this compound is a preferred product of the overall synthetic scheme of this   invention    However, this is for purposes of convenience and is not intended to limit the scope of this invention in any way. The details described in terms of this product are directly applicable to the full scope of the processes of this invention as described below or as routinely modified by those of skill in the art in view of conventional considerations and the guidelines given herein.



   In the foregoing, suitable alkyl groups   Rl-R4    are typically of 1-8 C atoms, preferably of 1-4 C atoms, and most preferably methyl or also ethyl. Other specific straight chain or branched alkyl groups include n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, a pentyl group, a hexyl group, a heptyl group or an octyl group. Preferably, at least one of   Rl-R4    is alkyl and most preferably, all four are alkyl groups.



   The substituents   R5    and R6 are generally non-critical to the successful carrying out of the various process steps as long as they are reaction-compatible, e.g., do not interfere with the underlying chemical reactions. Such interfering groups will be readily recognizable to those of skill in the art. Suitable R5 and   R6    groups, when present, include alkyl groups of 1-8 carbon atoms. All of the details discussed above with respect to R1-R4 alkyl groups apply here also. All of these alkyl groups R1-R6 can be the same, all can be different, or some can be the same and some different.

 

   Suitable aryl groups as R1, R2,   R3,      R4,    R5 and R6 are of, e.g., 6-10 C atoms and include hydrocarbons, e.g., phenyl, l-naphthyl, 2-naphthyl, etc. Heterocycles are equivalents thereof, e.g., of 1 or more fused rings (e.g., 1-3) typically of 4 to 7 ring members each, containing about 1-3 heteroatoms each, e.g.,   O,    N and/or S, e.g.,  thiophenyl, furanyl, imidazolyl, indolyl, pyrrolyl, etc.



  Further equivalent structures are those wherein R5/R6 form a fused ring of, e.g., 4 to 6 members, usually all C-atoms but also optionally including 1 to 3 hetero atoms, e.g., O,
N or S, preferably 5,6-benzo. In all cases, of course, the substituent   R1-R6    must be reaction compatible, e.g., any rings must be sufficiently electron rich that they will not be reduced during the   NaO/KO    reaction. Aralkyl groups include those, e.g., of 6-10 C-atoms in the aryl portion and 1-8 C-atoms in the alkyl portion, e.g., combinations of the aforementioned alkyl and aryl moieties. The aryl groups and fused rings can be substituted by a group such as alkyl (e.g., of 1-8 C atoms), carboxyl, hydroxy, alkoxy of 1-8 C atoms, alkylsulfonyl, amino, etc. The alkyl groups can also be similarly substituted to form equivalent groups.



  Again the substituent must not interfere with the subject reaction(s) or must be conventionally protected.



   The esterifying moieties R7 and R8 will generally also be alkyl groups of 1-8 C atoms, straight chain or branched.



  Again, all of the details regarding these alkyl groups discussed above with respect to R1-R4 apply here.



   Many other equivalent compounds will be applicable as starting materials in the processes of this invention and many will be obtainable as products. For example, a wide variety of compounds is included which differ from those literally described herein, e.g., by having one or more substituents protected by conventional, usually readily cleavable protecting groups, e.g., for OH, amino moieties, etc. Other equivalents include compounds containing compatible substituents or structural features, e.g., unsaturation, readily recognizable by those of skill in the art as applicable in the processes of this invention.



   The variety of substituents   R1-R8    is exemplified, e.g., in U.S. Patent 4,399,163, BP 1,434,043 and EP 0128654, which disclosures are incorporated by reference herein.  



   The ring contraction of an appropriately substituted cyclohexane derivative into a   cyclopentanederivative    can directly provide the desired carboxylic acid described above. This reaction can also provide a related material which can be conveniently converted into the desired acid or other derivative with a minimum amount of manipulation.



  This process can be represented schematically as follows:
EMI9.1     

The cyclohexane precursors are in turn more readily accessible from inexpensive commercially available substances than are the cyclopentanes.



   Such contractions per se are known. For example, see   "Carboxyclic    Ring Contraction Reactions", D. Redmore and C.



  David Gutshe in "Advances in Alicyclic Chemistry," 3, 1-138 (1971) which provides general guidance. See especially pages 125+. Its details are fully incorporated by reference herein. More specific examples related to "this particular system have been reported in Tetrahedron Letters (9), 759 (1979), F.   Kaplan    and M.L. Mitchell (see its
Scheme 2 (page 760) especially re tetramethyl-substituted compounds); and Annales Academiae Scientiarum Fennicae Ser.



  A 11 118, p. 4-52 (1962), D. Klenberg, which disclosures are also incorporated by reference herein.



   The reactions discussed below are related to these prior art disclosures only in that they involve a ring contraction from a cyclohexane group to a cyclopentane group. However, the reactions of this invention as described below involve surprising reaction results, often under surprisingly advantageous reaction conditions, and/or  
 with formation of surprising product(s) per se, and/or with
 surprising elimination of otherwise conventional reaction
 steps, e.g., in situ sequences have been discovered
 surprisingly to be utilizable while obtaining surprisingly
 high yields. The most preferred aspects of the process(es)
 of this invention will be described first.



   The conversion of adipate 3 to diketone 4 is achieved
 by acyloin condensation followed by in situ oxidation of
 the resultant cyclic acyloin to form the desired diketone.



   Acyloin condensations per se are known and discussed, e.g.,
 in the Annales Academiae reference cited above as well as
 in many standard organic texts, e.g., J. March, "Advanced
 Organic Chemistry," Third Edition, 1985, p.   1113.    Here,
 the reaction can be conducted using sodium or potassium metal, preferably sodium metal in an inert solvent.



  Reaction temperatures are suitable which allow the reduction to proceed at a reasonable rate. Typically, temperatures of   25-120     C are used. Typical reaction times are about 1-48 hours. Typically, 0.8-2.0 equivalents of
 the alkali metal is utilized. - Suitable solvents are well known and include diethylether, tetrahydrofuran, benzene,
 toluene, xylene or other solvents compatible with sodium.



   During preliminary experiments'on this aspect of the
 invention, it was noticed that the diketone was produced as
 a by-product of the acyloin condensation. It subsequently was determined, surprisingly, that the diketone could be
 obtained as a principal product by performing a subsequent oxidation in situ without isolation of any products from
 the acyloin condensation. The preferred oxidizing agent is thionyl chloride. However, many other oxidizing agents are suitable, including oxygen, chlorine, sulfuryl chloride, manganese dioxide, iodobenzene diacetate,
N-bromosuccinimide, N-chlorosuccinimide, chloroisocyanuric acid, chlorinated amines, hypochlorites and hypobromites,  including those of t-butyl, sodium, calcium, etc., sodium persulfate, diphenyl disulfide, elemental sulfur, etc.



   The in situ oxidation step is generally carried out at temperatures of -10 to   140OC    in the same solvents utilized in the first step, using about 1-8 equivalents of oxidizing agent. Typical oxidation times are less than one to 24 hours.



   Preferred conditions for the-cyclization step involve the use of about 1.1 equivalents of sodium in toluene at about   50 0C    for about 24 hours. Preferred oxidation conditions involve cooling the reaction medium resulting from the first step to about   00C,    adding the oxidizing agent and then warming to a reaction temperature of about 640 for about 4 hours. Overall yields for the cyclization/oxidation are very high, e.g., in the range of 90-100%, typically about   95*.   



   In another preferred step of the process of this application, hydrazone 5 is prepared from diketone 4 by reaction of the latter at   a pH    of 5-11 with hydrazine in the presence of an acid catalyst. It has been discovered that the pH of the reaction solution is critical to the achievement of high yields. The preferred pH range is 6-10,   especially,' 8-10.   

 

   In another surprising aspect of this reaction, it has been discovered that it is not necessary to carry it out under conditions which achieve continuous removal of water from the reaction. A priori, it was expected that this would have been necessary. Surprisingly, not only can the reaction be conducted at room temperature or even lower temperatures, but it even can be conducted using aqueous hydrazine solutions as starting materials. Thus, the reaction can be conducted without heating, preferably in the temperature range of   10-40 0C,    most preferably at about room temperature. Of course, it is still possible to carry  out the reaction at higher temperatures with continuous removal of water, but this is neither necessary nor economical.



   The reaction can be conducted in the presence of any of a large number of weak acidic catalysts, typically those having pKa values in the range of about 1-6, e.g., benzoic acid, acetic acid, propionic acid, trifluoroacetic acid, phthalic acid, etc. The dione is usually dissolved in a compatible solvent, typically an aromatic hydrocarbon solvent such as benzene, toluene or xylene in the presence of about 1-20 mole percent of the acid catalyst based on the amount of dione used. Also typically present is an alcohol, e.g., an alkanol of 1 to about 8 carbon atoms.



  The typical amounts of alcohol are 0-50%. Typical amounts of hydrazine are about 1-10 equivalents, i.e., usually an excess. The reaction time normally is from 2-24 hours.



  Reaction yields for this step are also high, e.g., in the range of about 90-100%, typically about 95%.



   Particularly preferred conditions involve the use of ten equivalents of hydrazine in toluene containing acetic acid and ethanol.



   Considering the use of excess hydrazine, it is also surprising that the monohydrazone is the major product.



  Monohydrazones are reported to be the product of reactions of hydrazine with aryl ketones. Generally, in reacting hydrazine with alkyl ketones, no useful product can be isolated, or the remaining NH2 group condenses with a second mole of carbonyl compound to give an azine, e.g.,
EMI12.1     
  
With a-diketones, an additional expected by-product is the osazone
EMI13.1     

No evidence for any of these side-reactions and products was noted in this invention. See J. March, "Advanced
Organic Chemistry," supra, pg. 84.



   In a highly preferred aspect of this invention, a diazoketone such as 6 is reacted with an amine directly to form the corresponding amide of the corresponding cyclopentane carboxylic acid. This reaction is especially surprising since the effect of the amine during the ring contraction could not be anticipated in view of the prior art knowledge that such a contraction per se produces not only the desired ring contracted ketene, but also an undesired by-product, the corresponding   a,P    - unsaturated ketone. See Kaplan and Mitchell, supra.

  Surprisingly, it has been found that direct reaction of the diazoketone with the amine under ring contraction condition produces very high yields of the desired ring contracted amide 12:
EMI13.2     
 as well as corresponding amides with substituents   Rl-R6    above,
 where each of   R9    and   R10    independently is H, alkyl, aryl or aralkyl.  



   Suitable amines for use in this step of the invention
 include all compatible primary or   secondary amines,e.g.,    ammonia, dimethylamine, methylamine, dibutylamine, aniline, phenylpropanolamine, etc. Such amines also include all of
 the important amino acids, including all of the naturally occuring amino acids as well as their optical isomers and
 racemates. Other amines correspond to the structures shown
 in U.S.P. 4,399,163, EPA-0128654, BP 1,434,043, which are
 incorporated by reference herein, as well as related
 disclosures concerning other synthetic sweetening agents.



  The   R9    and R10 moieties in the amines and resultant new amides generally include H and all of the alkyl, aryl,
 aralkyl, and alkaryl groups mentioned above or described in terms of alkyl or aryl components, as well as their
 substituted and equivalent counterparts. Many other   -possible    amines are also equivalents for use in this
 invention as will readily be recognized by those of skill
 in the art.



   Typically, from 1-2 equivalents of the amine is used to
 react with the diazoketone. Suitable solvents include
 benzene, toluene, xylene, chlorobenzene, chloroform,
 dichloromethane, carbon tetrachloride, tetrahydrofuran,
 dioxane, diethyl ether, dimethoxyethane, acetonitrile,
 benzonitrile, etc. The reaction is usually conducted at
 temperatures of 65-100   0C    for times of 2-4 hours.



   In cases where the amine reactant is unstable as a free
 base or is more conveniently available as an acid salt
 (e.g., the hydrochloride salt), it is acceptable to
 generate the amine base from its acid salt precursor in
 situ using a second base such as a tertiary amine (e.g.,
 triethylamine, N-ethylmorpholine, diazabicyclooctane, etc.)
 or an inorganic base such as the alkali metal carbonates or
 bicarbonates or alkaline earth metal oxides.  



   In this preparation of the amide 12 and that proceeding from ketene 8 described below, optical activity of the starting amine will be retained, e.g., where the amine is an   oically    active amino acid, e.g., a naturally occurring amino acid. Usually, retention of optical configurational purity is important for maintenance of the desired end-use property e.g., sweetness. Determination of optimal reaction conditions for retention of optical activity is routine and   known, e.g.,    in the field of peptide bond formation. For example, it is known that the identity of the acid scavenger can be important in this regard, e.g., often a morpholine-based scavenger will lead to higher retention of optical activity than other conventional agents such as triethylamine.

  Where the otherwise preferred preparation of the amide (12) directly from diazoketone (6) involves an unacceptably high degree of racemization, ketene (8) can first be prepared as described below prior to addition of the optically active amine. The ketene (8) can then be converted to amide (12) under the mild reaction conditions discussed below. This avoids exposure of the optically active compounds to the more highly reactive conditions used to prepare the ketene,' thereby lessening the likelihood of racemization.

 

   In another preferred aspect of this invention, the reaction of the amine and the diazoketone is conducted in situ in the reaction solution which results after hydrazone 5 is used to prepare diazoketone 6. This results in a highly advantageous one-pot preparation of the desired amide product starting with the hydrazone.



   Hydrazone 5 is converted to diazoketone 6 by oxidation.



  The reaction can be carried out by stirring a solution of the hydrazone in an inert solvent. Any of the common solvents compatible with the reagents involved can be used, e.g., toluene and its equivalents described elsewhere  herein and well known to those of skill in the art.



  Suitable oxidizing agents are   manganese, (IV)    dioxide, silver oxide, iodobenzene diacetate, etc. The reaction is normally conducted at a temperature of about   0-500C    for times of about 1-24 hours. Typically, about 1-10 equivalents of the oxidizing agent is utilized. In a preferred aspect, this step is carried out in a toluene solution of hydrazone 5 while stirring it at   25 0C    with three molar equivalents of activated manganese dioxide for 2 hours.



   Yields in this aspect of the process are also very high, e.g., in the range of   80-998    for both the reaction of the diazoketone with the amine and 90-100% for that of the hydrazone with the oxidizing agent. Typically, yields are around 95% for the hydrazone oxidation and, around 90% for the coupling of 6 with an amine.



   In especially preferred aspects of this invention, the foregoing preferred reactions are performed sequentially, e.g., diester 3 is used to prepare diketone 4 which is then used to prepare hydrazone 5. This sequence of reactions can then be extended whereby hydrazone 5 is used to prepare diazoketone 6; or, the sequence can begin with diketone 4 which is used to prepare hydrazone 5 which, in turn, is used to prepare diazoketone 6. Of course, the sequences ending with diazoketone can be extended in a direct preparation of an amide of a desired amine, e.g., most preferably by reaction with alanine methyl ester.



   Regarding the other reactions of the scheme shown above, the adipate (3) can be prepared by esterification of the corresponding acid (2) with an alcohol and an acid catalyst in such a way as to remove water as it is formed in the reaction. Suitable aliphatic alcohols which provide satisfactory esters for this synthesis are represented by those containing C1-C8 branched or straight hydrocarbon  chains. The acid catalyst can be sulfuric acid, an arylsulfonic acid such as toluene sulfonic acid, methane sulfonic acid or a polymeric resin sulfonic acid such as
Nafion-HR. Temperatures usually are   75-120 0C    and reaction times 4-24 hours. The esterification is typically carried out in a hydrocarbon solvent which forms an azeotrope with water. Examples include benzene, toluene or xylene.

  This, however, is not necessary when higher boiling alcohols that form azeotropes with water are used. An example is butanol. Preferred conditions involve dissolving the diacid (2) in a mixture of sulfuric acid, ethanol and toluene and slowly distilling off a tertiary mixture of toluene, ethanol and water until the theoretical amount of water has been collected. It will be recognized by those skilled in the art that any of the well known literature procedures for preparing esters from carboxylic acids apply to the synthesis of (3) within the scope of this invention.



   The adipic acid (2) can be prepared by one of several procedures known to the prior art. The preferred method for the purpose of this invention involves a procedure which is based on but constitutes a significant improvement over that reported by D.D. Coffman, E.L. Jenner and R.D.



  Lipscomb, J. Amer. Chem. Soc. 80, 2864 (1958).



   Pivalic acid is oxidatively dimerized by mixing with water and sulfuric acid. To this mixture is simultaneously added a solution of iron (II) sulfate in aqueous sulfuric acid and a solution of aqueous hydrogen peroxide.



  Temperatures usually are 25-100 C and reaction times 1-10 hours. Typically, from 1-10 molar equivalents each of hydrogen peroxide, ferrous sulfate and sulfuric acid are used, most preferably 1 equivalent each of hydrogen peroxide and ferrous sulfate and 1.3 equivalents of sulfuric acid. It has been determined in accordance with this invention that adding a small amount (e.g., 0.1 to  0.5% w/w based on pivalic acid) of a non-ionic surfactant (e.g., CONCO-100) of the low molecular weight polyethylene-oxide variety (e.g., molecular weights of about 250-2500) improves the quality of the product precipitate. The latter comes out of the reaction mixture in a gummy, taffy-like consistency when the surfactant additive is omitted. This product would be very difficult to process otherwise.

  In addition, in accordance with this invention, it has been found that conventional ammonia treatments used in the workup of the crude product to remove iron salts can be omitted. The   crude-precipitate    from the reaction mixture can be simply crystallized from methanol. This greatly simplifies, shortens and cuts the costs of the procedure not to mention reducing the amount of wastewater generated by the process. Ionic surfactants can also be used including anionic and cationic ones.



  Non-limiting examples of such surfactants include dialkylsulfosuccinates, e.g., a dioctylsulfosuccinate, long-chain alkylbenzene sulfonates, e.g., sodium   dodecylbenzene    sulfonate, etc.



   In cases where the preferred method above is inapplicable (e.g., where R5/R6 is a fused component), many options are available for the synthesis of diacids (2) and the corresponding diesters (3) possessing the variety of substituents R1-R6 specified above. For example, many members of the class of compounds can readily be prepared by the familiar Koch-Haaf reaction when the appropriate diol, diene, dihalide or hydrocarbon is accessible (see "New Syntheses with Carbon Monoxide," J. Falbe, Ed.,
Springer-Verlag Publishers, 1980, Chapter 5). Many members can be prepared by an alkylation of the anion derived from an enolizable ester or nitrile. This approach is useful in preparing diesters which are more highly substituted alpha to the ester function from those which are less substituted.

  The above discussion merely serves as an  example of the types of reactions that are conventional to those skilled in the art. A multitiude of others are possible in preparing the compounds (2) and/or (3) mentioned in this specification. For all reactions mentioned herein for preparation of starting materials, e.g., (2), the starting materials required are conventional per se or can be routinely prepared from known or readily preparable starting materials using conventional reactions.



   Simply heating a solution of diazoketone (6) in a substantially anhydrous non-hydroxylic solvent causes thermal rearrangement with evolution of nitrogen, producing ketene (8) which can be viewed as a functional equivalent of acid (7) for the ultimate uses for this compound.



  Appropriate solvents for this transformation are those which have a boiling point equal to or greater than the temperatures necessary to bring about rearrangement and are otherwise reaction compatible. Some examples of solvents which satisfy the criteria for this reaction are tetrahydrofuran, dioxane, benzene; toluene, xylene, dichloroethane and chlorobenzene to name a few. A practicable temperature range for ketane formation is 60  to 140 C. Reaction times typically are 1-7 hours.

 

  Preferred conditions employ toluene as solvent, at 900C.



  Yields are excellent, e.g.,   90-1008,    typically around 95%.



  An advantage of this approach is that the solution of the ketene produced can be used directly as an acylating agent.



  In this regard, ketenes, due to their extremely high reactivity, allow the use of very mild reaction conditions.



  In particular, ketene (8) can be hydrolyzed to the acid (7) or reacted with an amine such as those already described herein to produce amide (12) at a temperature in the range of   -200C    to   25 0C.    Of course, higher temperatures are also effective. Other reaction parameters are the same as those described for the analogous transformations beginning with the diazoketone (6). A further advantage of this approach  is revealed in the case where the amine being acylated is optically active and susceptible to racemization as discussed above. This function (high reactivity) can only be achieved alternatively by preparing and isolating acid (7) and then converting it to an activated form in a separate step.



   The carboxylic acid (7) can also be produced from (6).



  For example, it can be accomplished by dissolving diazoketone (6) in aqueous alkaline media containing an organic co-solvent and then heating the homogeneous solution to a temperature sufficient to bring about rearrangement and hydrolysis. Typical temperatures are 65-100 C and reaction times 2-8 hours. Compatible co-solvents are those which exhibit appreciable water solubility such as lower alcohols, ethylene glycol, acetonitrile, tetrahydrofuran, dioxane, dimethylsulfoxide, and the like. A suitable aqueous alkali is sodium or potassium hydroxide solution. Alternatively, a solvent which is substantially immiscible with water can be used in combination with a phase transfer catalyst such as tetra-n-butylammonium ion, 18-crown-6, etc., as is known.



  Equivalents of these reactants and conditions are clear to skilled workers. For example, the reaction can be performed successfully (albeit more slowly) in the absence of the alkaline reagent. The preferred conditions for this reaction make use of ethanol as co-solvent mixed in a ratio of 3:1 with 18.75% (w/w) sodium hydroxide solution. The reaction mixture is refluxed for two hours to afford (7).



  Of course, the reaction of (6) to prepare (7) can also be carried out in situ of the   reaction(s)    used to prepare (6) from (5). See, e.g., Example 10 below.



   Another method of obtaining acid (7) from dione (4) is to convert the dione into the ring-contracted hydroxy-acid (9) or ester (10). The reaction can be realized by treating (4) with sodium hydroxide or alkoxides in water or  alcohol solvents. This reaction is run in a nitrogen atmosphere at a temperature of   650-1000Cfor    1-18 hours.



     Alcohol/alkoxide    combinations which are useful in this process are those containing one to eight carbon atoms in each component. In the case where the acid (9) is produced, it can be converted to an ester in a separate step, e.g., a   C1 8-alkyl    ester. These esters, of which (10) is a representative example; are used to prepare the acylhydrazide (11). This can be accomplished by heating the ester (10) at 90-140 C for 6-48 hours with excess hydrazine in the presence of a solubilizing agent which renders the reaction mixture a homogeneous solution. More specifically, from one to ten equivalents of hydrazine can be employed in a volume of a high boiling alcohol equal to the volume of hydrazine used.

  Examples of such alcohols are butanol, ethylene glycol and its homologs or other alcohols with boiling points greater than   1000C.    Preferred conditions include heating (10) with four equivalents of hydrazine in n-butanol at 1050C for twenty hours.



   The acid hydrazide prepared by this method can be used to synthesize acid (7) by an oxidative procedure. In this procedure, the hydrazide is exposed to a reagent capable of converting the hydrazo moiety into the azo moiety. Most surprisingly, this reaction results in splitting off water at the same time and consequently preparing the acid (7).



  Many familiar oxidizing agents known in the prior art can be used. These can be employed stoichiometrically or in excess. Non-limiting examples of these include halogens such as chlorine or bromine, silver or mercury oxides, manganese dioxide and others.



   Conditions employed depend upon the oxidizing agent used. A description that illustrates the nature of those which are generally practical is as follows: The reaction is carried out in the temperature range of   00-1000C    in  either water or organic solvents or mixtures of the two.



  Acceptable organic solvents include those such as the C1-C4 alcohols, glycols such as ethylene glycol or propylene glycol, ethers such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane. Other useful solvents are acetonitrile and dimethylformamide. A preferred mode of this reaction comprises adding a solution of sodium hypochlorite to an aqueous mixture containing the hydrazide (11) at a temperature of 0 C followed by warming to 25 C for one o hour. Nitrogen gas is evolved, affording compound (7).



   The product (7) formed in any of the ways described above can be used directly in many prior art reactions for preparation of many useful compounds. Alternatively, the acid can fully conventionally be converted into any of its well-known functional equivalents such as any of the acid halides. Use of the acid products of this invention to prepare the desired known prior art products is fully conventional. See Fuller, Goodman and Verlander, supra, and The Chemistry of Functional Groups Series, Saul Patai
Editor, "The Chemistry of the Carboxyl Group," Wiley
Interscience, 1966.



   Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. In the preceding text and the following examples, all temperatures are set forth uncorrected in degrees Celsius and all parts and percentages are by weight, unless otherwise indicated.  



   Example 1
 2,2,5,5-Tetramethyladipic   Acid(2)   
 To a 5.0 1, 3-neck baffle flask, equipped with agitator, thermometer and two dropping funnels is charged 2,282 ml water, 28.5 ml sulfuric acid and 195.0 g (1.91 mol) of pivalic acid. Conco 100 (0.25 ml) and, while vigorously agitating the mixture, 295 ml of a 6.67 molar solution of hydrogen peroxide and 1432 ml of a 1.33 molar ferrous sulfate solution (previously purged with nitrogen for 30 minutes) that contains 105 ml H2SO4, are added simultaneously via calibrated dropping funnels. The reaction mixture is maintained at 35-400C with an ice bath during the 15 min. addition time. At the end of the addition time 1100 ml of a mixture of pivalic acid and water is distilled from the reaction flask.

  The flask contents are cooled to 200C and the crude   2,2,5,5-tetramethyladipic    acid is isolated by filtration, washed with water and dried; weight 73.0 g. The 73.0 g of diacid crystallized from 73 ml of methanol gives 44.0 g 2,2,5,5-tetramethyladipic acid, mp   181-1840C,    neutralization equivalent 101; theory, 101.1.

 

   Example 2
   Diethyl-2,2,5,5-Tetramethyladipate    (3)
 A total of 186.0 g (.92 mol) of 2,2,5,5-tetramethyladipic acid, 1350 ml toluene, 450 ml ethanol and 4.75 ml (0.09 mol)   E2SO4    is placed in a 3.0 1 flask equipped with a pot thermometer, vapor thermometer, stirrer, and condenser with
Vigreux column and Dean-Stark tube. The flask is heated to gentle reflux to collect an azeotropic mixture of ethanol, toluene and water which distills at   74.2 -75 C.    A total of 545 ml of distillate is collected containing 35 g   H2O    vs expected 33.1 g H2O. The temperature is increased and 400 ml of solution (ETOH-toluene) is'distilled off. The solution is cooled to     5-10 C,    and 60.0 g of 16.7% Na2CO3 solution is slowly added.

  The organic layer is separated and washed with three 100 ml portions of saturated NaHCO3 solution. The toluene layer is dried over Na2SO4. After atmospherically distilling off the toluene, diethyl 2,2,5,5-tetramethyladipate is isolated by vacuum distillation, b.p. 95-980C at 2 torr. through a short
Vigreux column. The yield is 196.0 g, 82.7% of theory.



   Example 3    2-Hydroxy-3 ,3,6, 6-Tetramethylcyclohexanone   
 To a stirring solution of 41.0 g (1.78 mol) of sodium beads in 176 ml of dry toluene maintained under dry nitrogen is slowly added a solution of   81.t    g (.314 mol) diethyl 2,2,5,5-tetramethyladipate in 229 ml of toluene at   25 -30 C    over a 45 minute period. There is a slight exotherm during the ester addition. The reaction mixture is maintained at 45-50 C for 20 hours. The gelatinous mass is cooled to   5-10 C    under N2 and 250 ml of 35% H2SO4 is cautiously added. Layers arse separated and the organic layer dried over   Na2SO4.    Toluene is distilled off and the product vacuum distilled.

  Yield is 34.0 g of 2-hydroxy-3,3,6,6-tetramethylcyclohexanone, bp 82-850C at 8 to 10 torr;   63.4%    theory; mp 290-310C.



   Example 4
   3,3,6,6-Tetramethylcyclohexane-1,2-Dione    (4)
 To a stirring solution of 68.0 g (.397 mol) of   2-hydroxy-3,3,6,6-tetramethylcyclohexanone,    67 ml dry pyridine and 520 ml dry toluene that has been cooled to   0    to 50C under a N2 atmosphere is slowly added 240 ml (3.3M)   
 0 of thionyl chloride maintaining a temperature of 10 C or    less.

  After addition of SOCl2, the reaction mixture is gently heated at 60-650C for 12 hours.   The,reaction    is  cooled to   20 0C    and then slowly added to a stirring mixture of crushed ice and water (about 1,250   ml);    The layers are separated and the toluene layers washed with 500 ml saturated NaCl, two 500 ml portions of saturated   NaRCO3,    and finally with 500 ml saturated   Nazi.    The toluene solution is dried over Na2SO4 and concentrated by rotary evaporation to dryness. A 100-ml portion of cyclohexane is added to the residual yellow solid. The product is collected by filtration and washed with 10 ml cyclohexane.



  Yield is 54.0 g of   3,3,6,6-tetramethylcyclohexane-1,2-dione,    yellow crystals, mp   1120-1130C,    81.0% of theory.



   Example 5
 Preparation of Tetramethylcyclohexane-1,2-Dione (4)
 Diethyl 2,2,5,5-tetramethyladipate (25.8 g, 0.10 mol) is added to a vigorously stirred suspension of sodium (9.2 g, 0.40 mol) beads in toluene under a nitrogen atmosphere at 25 C. After complete addition, the temperature is brought to   50 0C    and maintained for 24 hours. The thick gelatinous mixture is then cooled in an ice bath and thionyl chloride is added drop-wise. Cooling is maintained but the temperature is allowed to rise to   65 0C.    This is maintained for 30 minutes. The excess thionyl chloride and toluene are then recovered by distillation and the residue is slurried two times with hexanes to remove diester. The residue (13.1 g, 0.078 mol) is composed of almost pure dione and represents a 78% yield.



   Example 6
 Preparation of tetramethylcyclohexane-1,2-dione (4)
 The procedure in Example 5 is followed exactly until the thionyl chloride addition. At this point, the reaction flask is cooled in a dry ice-acetone bath. When the  internal temperature reaches   -10 0C,    thionyl, chloride is introduced slowly as a 50% (v/v) solution in toluene. The temperature during addition is not allowed to exceed 4    C.   



  When addition is complete, the internal temperature is brought up to 650C and held at this temperature for 12 hours. The mixture is then allowed to cool to ambient temperature. It is then extracted two times with water and two times with saturated sodium bicarbonate solution. The toluene phase is dried over anhydrous magnesium sulfate, filtered and concentrated to give the solid dione, 15.8 g, 94% yield, m.p.   1060-1080C.   



   Example 7
 Preparation of Monohydrazone of 3,3,6,6
   Tetramethylcyclohexane-l, a-Dione    (5)
   Rydrazine    (14.0 g, 0.44 mol) is added slowly (exothermic) to a stirred solution of the   3,3,6,6,-tetramethylcyclohexane-l,2-dione    (6.73 g, .04 mol), ethanol, 25 ml and benzene, 50 ml in a flask fitted with a Dean-Stark apparatus for azeotropic removal of water. After addition of hydrazine is complete   (15     temp.



  rise noted), acetic acid is added and the mixture refluxed with continuous removal of water. The theoretical amount (0.8 ml) is obtained in 8 hours. The reaction mixture is allowed to cool to room temperature. It is then extracted three times with 100 ml-portions of water, followed by two times with 50-ml portions of saturated NaCl solution. The organic layer is dried over anhydrous Na2SO4, filtered and concentrated giving 7.19 g of the monohydrazine as a yellow solid, mp 87.5-89.50C. NMR and IR data consistent with expected product.  



   Example 8
 Preparation of   Monohydrazone of 3,3,6,6-   
   tetramethylcyclohexane-1 , 2-dione    (5)
 A 100-ml round-bottom flask equipped with magnetic stir bar is charged with the dione (4), 1.68 g (0.01 mole); toluene, 12.5 ml; ethanol, 7.5 ml and acetic acid, 2.5 mcl.



  While stirring at room temperature, 64% (w/w) aqueous hydrazine, 5.50 g (0.11 mole)-is added. The resulting mixture is allowed to stir at ambient temperature.



  Reaction progress is monitored by thin layer chromatography (silica gel; 1% ethyl acetate in dichloromethane as eluent). After 2.5 hours the dione (4) is completely converted to the hydrazone (5). The two phase mixture is separated. The top phase containing the hydrazone is washed three times with fresh portions of water (5 ml each) then dried over anhydrous sodium sulfate. Filtration of the dry solution followed by evaporation of the solvent produces 1.81 g of essentially pure hydrazone. The yield is 99%. This material is crystallized from an ethanol-water mixture giving yellow needles, m.p.

 

     93.20C-94.5QC.    The crystalline hydrazone is further characterized by the following spectral properties:
 NMR - 60 MHz,   CC14    solution
 ppm downfield from TMS: 1.10, S; 1.13, S (12 H); 1.68,
 S   (4H);    9.1, br.s   C2H)   
 IR - CC14 solution (selected bands)
   -1    3480, 3210, 2960, 2930, 2860, 1670, 1530,   1465,   
 1450, 1378, 1355, 1097, 1007.



   Example 9
 Preparation of Diazoketone (6)
 A solution of the hydrazone (5) (0.6 g, 3.29 mmol), in 8 ml benzene is added over 30 minutes to a stirred  suspension of   Mono2(0.99    g, 11.39 mmol) and   MgSO4    (1.65g) in 8.5 ml benzene at room temperature.   TLC analysis    reveals that the hydra zone is completely consumed in 2 hours producing the diazoketone contaminated with only minor impurities. The reaction mixture is allowed to stand overnight. It was then filtered and the filtrate concentrated to a residual yellow oil weighing 0.57 g. The oil is characterized by NMR   and    IR spectra. A chromatographically homogeneous product is obtained by flash chromotography, 0.28 g (46% yield).



   Example 10
 Preparation of   2,2,5,5-Tetramethylcyclopentane-   
 l-Carboxylic Acid   (TMCP-CO2H)    (7)
 The monohydrazone of   3,3,6,6-tetramethylcyclohexane-    1,2-dione (26.10 g 0.14 mol) in benzene (23.49 g) solution is slurried with manganese dioxide   (43.01    g,   0.49-mol)    and the result stirred at room temperature for two hours. The solids are filtered off and the filtrate concentrated to an oily residue. This is dissolved in 4 ml ethanol and the solution added to the aqueous sodium hydroxide solution with stirring at 25 C. The mixture is in two phases so an additional 2 ml ethanol is added to achieve homogeneity.



  At this point, the solution is heated to reflux (gas evolution evident at 750C) for two hours. Upon cooling to   25 0C,    the ethanol is removed in vacuo. The aqueous residue is acidified and extracted with ether. The ethereal extract is then   dried-over    anhydrous MgSO4, filtered and concentrated to give the tetramethylcyclopentane-lcarboxylic acid as an off-white solid (23.49 g, 0.137 mole), mp   125.5 -128 C.    The yield is 96% from the hydrazone. The NMR spectrum of the above product indicates that it is virtually pure TMCP-CO2H.  



   Example 11
 Preparation of   2,2,5, 5-Tetramethylcyclopentane-   
 Carboxylic Acid (7)
 A 25% sodium hydroxide solution (9.4 ml) is charged in a 25 ml 3-neck round bottom flask equipped with thermometer, reflux condenser and magnetic stir bar. The entire apparatus is purged and maintained under an N2 atmosphere. While stirring vigorously, a solution of the diazoketone (6) (0.275 g, 1.5 mmol) in ethylene glycol (3 ml) is added dropwise. An emulsion results and the mixture is heated to reflux for two hours. The yellow solution obtained is cooled to room temperature and extracted three times with ether. It is then acidified and extracted again with three 20 ml portions of ether which are combined and extracted twice with water and twice with saturated sodium chloride.

  Drying of the ethereal solution over MgSO4, filtration and concentration affords 0.238 g of crude product. This weight corresponds to 91% of that expected for a theoretical yield. NMR analysis of this material suggests that 50% of it is the desired acid, giving an overall yield of   458.    A crystalline sample is isolated from the petroleum ether solution of the crude product. It is identical in all respects with an authentic sample of the acid.



   Example 12    (L)-Methyl-N-(2,2,5,5-tetramethylcyclopentane-l-carbonYl)-   
 alaninate (Method 1)
 A solution of the diazoketone (6) (1.8 g, 10 mmol) in 5 ml of toluene is added to a stirring suspension of
L-alanine methyl ester hydrochloride (1.39 g, 10 mmol) and triethylamine (1.39 ml, 10 mmol) in 5 ml toluene. The resulting reaction mixture is then heated at   90 0C    for three hours. Upon cooling to ambient temperature, the mixture is  washed once with 5% aqueous hydrochloric acid, once with water and once with saturated aqueous sodium bicarbonate solution. The toluene solution is then dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid residue of 1.74 g of (L)-methyl   N-(2,2,5,5-tetramethylcyclopentane-1-carbonyl)alaninate.   



  The coupled product obtained is about 90% pure.



   Example 13
   2,2,5,5-tetramethylcyclopentane-1-carboxylic    acid amides
 The procedure of Example 12 was followed using the following instead of   ;it±-alanine    ester hydrochloride: methylamine hydrochloride, dimethylamine, aniline, di-n-butylamine and phenylpropanolamine hydrochloride.



  The procedure also varied in that in the case of methylamine 3 equivalents each of the amine reactant and of triethylamine were used; and the dimethylamine was added as a 22% aqueous solution, i.e., a two-phase reaction ensued.



  Where the amines per se were used, triethylamine was not employed. The following amides were obtained (% yield; m.p.   (OC)),    respectively:   N-methyl-2, 2,5, 5-tetramethylcyclopentane-1-carboxamide,    (84%; 170-173.5)   -   
 NMR: ppm downfield from TMS: 1.13,   s(l2H);    1.58,
 m(4H); 1.85, s(lH); 2.8, d(3H); 5.66, brs(lH)
 IR (selected bands, cm 1): 3475, 3360, 2990, 2950,
 2870, 1665, 1505, 1460, 1410, 1385, 1367, 760(br)   
N,N-dimethyl-2,2,5,5-tetramethylcyclopentane-1-carboxamide    (67%; oil)
 NMR: ppm downfield from TMS: 1.05,   d(12H);    1.58,
 m(4H); 1.85,   s(lE);    3.0, d(6H)
 IR (selected bands, cm 1):

   2960, 2880, 1650, 1460,
 1415, 1392, 1388, 1370, 1132   N-phenyl-2,2,5,5-tetramethylcyclopentane-1-carbOxamide      (86%;    115.5-117.5).  



   NMR: ppm downfield from TMS:    1.15, d(12H); 1.6,   
 m(4H); 2.0, s(1H); 7.3, m(6H)
 IR (selected bands, cm-1): 3440, 2950, 2870, 1685,
 1598, 1507, 1460, 1432, 1385, 1365, 1302, 1150; 1140,
 760(br)   
N,N-di-n-butyl-2,2,5,5-tetramethylcyclopentane-1-carboxamide    (76%; oil)
 NMR: ppm downfield from TMS: 1.07, m(22H); 1.55,
 m(8H); 1.86, s(lH); 3.21, m(4H)
 IR (selected bands,   cm 1): 2960,    2880, 1650, 1460,
 1415, 1392, 1388, 1370, 1132   
N-(i-hydroxyl-l-Qhenyl-prop-2-yl)-2,2,5,5-tetramethylcyclo-    pentane-l-carboxamide (76%; 122-122.8)
 NMR: pptn downfield from TMS: 1.1, m(lSH); 1.55,
 m(4H); 1.8, s(lH); 1.63, quart(lH); 4.27,   m(lH);    4.75,
   d(lH);    5.65, m(lH); 7.3, s(5H)
 IR (selected bands,   cm 1):

   3435,    3380(br), 2945, 2860,
 1650, 1490, 14-55, 1383, 1364, 750(br)
 Example 14 (L)-Methyl-N-(2,2,5,5-tetramethylcyclopentane-1-carbonyl)
 alaninate (Method 2)
 A solution of hydrazone (5) (1.82 g, 10.0 mmol), in 8 ml benzene is added over 30 minutes to a stirred suspension of MnO2 (3.0 g, 34.62 mmol) and MgSO4 (5.02 g) in 8.5 ml benzene at room temperature. TLC analysis reveals that the hydra zone is completely consumed in 2 hours producing the diazoketone contaminated with only minor impurities. The reaction mixture is allowed to stand overnight. It is then filtered and the solution of the diazoketone is added to stirring suspension of alanine methyl ester hydrochloride (1.39 g, 10 mmol) and triethylamine (1.39 ml, 10 mmol) in 5 ml toluene. The resulting reaction mixture is then heated at   90 0C    for three hours. 

  Upon cooling to ambient temperature, the mixture is washed once with 5% aqueous  hydrochloric acid, once with water and once with saturated aqueous sodium bicarbonate solution. The toluene solution is then dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid residue of 1.74 g of (L)-methyl   N-(2,2,5,5-tetramethylcyclopentane-1-carbonyl)-    alaninate. The coupled product obtained is about   908    pure.



   Example 15
Preparation of   2,2,5,5-Tetramethylcyclopent-l-ylidenone    (8)
 A solution of the diazoketone (6) (1.80 g, 10 mmol) in 10 ml dry toluene is heated at   900C    until its presence can no longer be detected by thin layer chromatography. This requires 3 to 4 hours. The resulting solution, upon cooling to ambient temperature is used directly to acylate primary and secondary amines or is hydrolyzed to acid (7).



   Example 16   l-Hydroxy-2 , 2,5, 5-tetramethylcyclopentanecarboxylic    Acid (9)
 A total of 16.8 g (.1 mol) 3,3,6,6-tetramethylcyclohexane-1,2-dione is added to 788 ml of 4 N NaOH in a 2.0 1 pressure bottle. The solution is saturated with N2 and the agitated solution heated while maintaining a pressure of 5 psi of N2 pressure at   110 0C    for 24 hours. The reaction mixture is cooled to   25 0C    and the alkaline solution extracted with two   100-ml    portions of methylene chloride.



  The extracted solution is acidified with 285 ml of concentrated   HCl.    The acidified solution is extracted with three   100-ml    portions of methylene chloride. The combined
CH2C12 extracts are dried over Na2SO4 and evaporated to dryness. Yield 12.0 g; l-hydroxy-2,2,5,5-tetramethylcyclopentane-l-carboxylic acid, mp   74-76 0C,    off-white crystals, 64.0% theory.  



   Example 17
 Preparation of methyl 2,2,5,5-tetramethyl-1
   hydroxycyclopentanecarboxylate    (10
 The hydroxyacid (9) (0.37 g, 2.0 mmol) is charged to a 50 ml round-bottom flask (polished joint) equipped with magnetic stir bar. A total of 5 ml of ether was added and stirring of the resulting solution was initiated. An ethereal solution of diazomethane is generated from
N-methyl-N-nitroso-p-toluenesolfonamide according to the procedure described in Aldrichemica   Acta    16 (1), 3 (1983).



  The generated diazomethane solution is distilled as it is formed, directly into the solution of the hydroxyacid.



  This is continued until the reaction solution takes on a persistent yellow color. At this point the solution is boiled in a stream of nitrogen until the color fades. The remaining solution is concentrated to a residual oil, 0.49g of pure ester (10).



   The ester (10) is characterized by its NMR and IR spectral properties:
 NMR: 60 MHz,   CDC13    solution ppm downfield from TMS:
 0.92,   s(6H);    1.1, s(6H); 1.75, br.s(4H); 3.37,   sClH);   
 3.8, s(3H)
 IR: CCl4 solution (selected bands)
 cm-1: 3630, 3540, 3000, 2970, 1755, 1725, 1475,
 1390, 1230, 1162, 1115
 Example 18
 Preparation of   l-Hydroxy-2,2,5,5-tetramethyl-   
 cyclopentanecarboxylic Acid Hydrazide (11)
 A mixture of the methyl ester (10) (2.0 g, 10 mmol), anhydrous hydrazine (1.28 ml, 40 mmol) and n-butanol (1.0 ml) is heated at 1000-1050C with stirring in a nitrogen atmosphere under a reflux condenser for 20 hours. The mixture is then allowed to cool to ambient temperature and  the excess hydrazine and butanol is removed under vacuum.



  The product, a viscous oil, is partitioned between water and dichloromethane. The phases are separated and the aqueous phase concentrated to a residual oil under vacuum.



  This material is used directly in the oxidation step using sodium hypochlorite. The hydrazide is characterized in this material by its NMR and IR spectral properties:
 NMR: 60 MHz,   CD3OD    solution
 ppm shift downfield from TMS: 1.1, br.s.(12H); 1.75,
   br.m(4H);    4.8, s.exch.



   IR:   CHC13    solution   (O.lg/cc)   
   cm'l:    3340, 3080, 3000-2900 br, 2860, 2800-2400 br,
 2350, 1700-1500   tr,    1455, 1375, 1335, 1150, 1075.



   It can be conventionally isolated and purified, e.g., using chromatographic techniques.



   Example 19
 Preoaration of   2,2,5, 5-tetramethvlcvclooentane-   
 carboxYlic acid (7)
   2,2,5,5-ttramethyll-hydroxycyclopentan    carboxylic acid hydrazide (11)   (0.035g,    0.18 mmol) is placed in a 5 ml round-bottom flash equipped with magnetic stir bar. A total of 100 mcl of water was added and the milky solution cooled by immersing the flask in an ice-water bath. While stirring the solution, an aqueous solution of sodium hypochlorite   (8.378    w/w) (157 mcl, 0.176 mmol) was added dropwise. Vigorous gas evolution was noted and a precipitate formed. After complete addition of the hypochlorite, the mixture was allowed to warm to ambient temperature. It was diluted with 100 mcl of water and the result   (pE    7) extracted twice with ether.

  The aqueous phase was acidified to a pH of less than 1.0 using concentrated hydrochloric acid. The solution, which had become clear after ether extraction and prior to acidification again takes on a milky appearance.  

 

  This was. extracted twice with ether and the organic extract concentrated to dryness leaving'5.4 mg of residue. The presence of the acid (7) was detected by thin layer chromatography by comparison with an authentic sample.



   The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.



   From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. 

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a diketone of the formula EMI36.1 wherein each of R1, R2, R3 and R4 independently is H, or optionally substituted alkyl, aryl or aralkyl and each of R5 and R6 independently is H, or optionally substituted alkyl, aryl or aralkyl or together R5 and R6 form a fusedring, comprising condensing the corresponding compound of the formula EMI36.2 wherein each of R7 and R8 independently is alkyl, in the presence of NaO or KO to form the corresponding cyclic acyloin and in situ oxidizing the latter product with an effective oxidizing agent to form the diketone as a major product.

2. A process of claim 1, wherein the first step is carried out in the presence of NaO, R5=R6=H, and R1=R2=R3=R4=CH3.

3. A process of claim 2, wherein the corresponding step is carried out using 0.8-2.0 equivalents of NaO at 25-1200C in a compatible solvent and the oxidation is carried out at -10 to 1400C in a" compatible solvent.

4. A process of claim 3, wherein the oxidizing agent is thionyl chloride, chlorine, sulfuryl chloride, oxygen, manganese dioxide, sodium persulfate or chloroisocyanuric acid.

5. A process for preparing a hydrazone of the formula EMI37.1 wherein each of R1, R2, R3 and R4 independently is H, or optionally substituted alkyl, aryl, or aralkyl and each oE R5 and R6 independently is H, or optionally substituted alkyl, aryl or aralkyl, or together R5 and R6 form a fused ring, comprising reacting the corresponding diketone of the formula EMI37.2 with hydrazine in the presence of an effective acid catalyst at a pH of 5-11, thereby obtaining the hydrazone as a major product.

6. A process of claim 5, wherein R5=R6=H and R1=R2 =R3=R4=CH3.

7. A process of claim 6, wherein the acid catalyst has a pKa of about 1-6, it is used in an amount of 1-20 mole%, the reaction is conducted in the presence of an alcohol and a compatible solvent, and the amount of hydrdzine is 1-10 equivalents.

8. A process of claim 5, conducted without heating.

9. A process of claim 5, conducted without any special measures to achieve removal of H2O from the reaction.

10. A process of claim 6, conducted without any special measures to achieve removal of H2O from the reaction.

11. A process of claim 10 carried out at about room temperature.

12. A process for preparing a cyclopentanecarboxamide of a primary or secondary amine of the formula EMI38.1 wherein each of R1, R2, R3 and R4 independently is H, or optionally substituted alkyl, aryl, or aralkyl and each of R5 and R6 independently is H, or optionally substituted alkyl, aryl or aralkyl, or together R5 and R6 form a fused ring, comprising reacting the corresponding diazoketone of the formula EMI39.1 with the amine, thereby obtaining the cyclopentanecarboxamide as a major product.

13. A process of claim 12, wherein R5=R6-E and R1=R2=R3=R4 3=R4=CH3.

14. A process of claim 13, wherein the diazoketone is reacted with the amine as a hydrochloride in the presence of triethylamine or N-ethylmorpholine.

15. A process of claim 12, wherein the amine is L-alanine or a derivative thereof.

16. A process of claim 13, wherein the amine is L-alanine or a derivative thereof.

17. A process of claim 14, wherein the amine is L-alanine or a derivative thereof.

18. A process of claim 12, wherein said reaction is carried out in situ in the reaction medium which results from preparing said diazoketone by oxidizing the corresponding hydrazone with a compatible oxidizing agent.

19. A process of claim 12 further comprising preparing the diazoketone by oxidizing with a compatible oxidizing agent the corresponding hydrazone of the formula EMI40.1 and then carrying out the reaction of the diazoketone and amine or amine hydrochlorid in situ.

20. A process of claim 5, further comprising preparing said diketone by condensing the corresponding compound of the formula EMI40.2 wherein each of R7 and R8 independently is alkyl, in the presence of NaO or KO to form the corresponding cyclic acyloin and then in situ oxidizing the latter product with an effective oxidizing agent to form the diketone.

21. A process of claim 19 further comprising preparing said hydra zone by reacting the corresponding dike tone with hydrazine in the presence of an effective acid catalyst at a pH of 5-11, and preparing said diketone by condensing the corresponding compound of the formula EMI41.1 wherein each of R7 and R8 independently is alkyl, in the presence of Na or K to form the corresponding cyclic acyloin and then in situ oxidizing the latter product with an effective oxidizing agent to form the diketone.

22. A process of claim 19 further comprising preparing said hydra zone by reacting the corresponding diketone with hydrazine in the presence of an effective acid catalyst at a pE of 5-11.

23. A process of claim 20 wherein R5=R6=H and R1=R2=R3 =R4=methyl.

24. A process of claim 21 wherein R5=R6=E and R1=R2=R3=R4=methyl.

25. A process of claim 24, wherein the amine is L-alanine or a derivative thereof.

26. A process of claim 22 wherein R5=R6=E and R1=R2=R3=R4=methyl.

27. A process of claim 26, wherein the amine is L-alanine or a derivative thereof.

28. A process for preparing a cyclopentane carboxylic acid of the formula EMI42.1 wherein each of R1, R2, R3 and R4 independently is H, or optionally substituted alkyl, aryl or aralkyl and each of R5 and R6 independently is H, or optionally substituted alkyl, aryl or aralkyl or together R5 and R6 form a fused ring, ring, comprising treating the corresponding diazoketone of the formula EMI42.2 under conditions effective to contract the six-membered diazoketone ring to form the five-membered ring of said cyclopentane carboxylic acid.

29. A process of claim 28, wherein R5=R6=H and R1=R2=R 3=R4=CH3.

30. A process for preparing a cyclopentane carboxylic acid of the formula EMI42.3 comprising reacting the corresponding hydrazide of the formula EMI43.1 with an oxidizing agent effective to convert the hydrazo group into an azo group.

31. A process of claim 30, wherein R5=R6=E and R1=R2=R3=R4=CH3.

32. In a process for preparing adipic acid or an alkyl or aryl derivative thereof by oxidatively dimerizing the corresponding pivalic acid compound thereby forming said adipic acid or derivative thereof as a precipitate, the improvement wherein the dimerization is conducted in the presence of an amount of a surfactant effective to enhance the separability of the precipitate from the reaction medium.

33. 3,3,6,6-Tetramethylcyclohexane-1-one-2-hydrazone.

34. A compound of the formula EMI43.2 wherein each of Rg and R10 independently is H, C1 8-alkyl, C6-10-aryl or C6-10-ar-C1-8-alkyl or wherein NR9R10 is a residue of a naturally occurring amino acid.

35. A compound of claim 34, which is N-methyl-2,2,5,5tetramethylcyclopentane-1-carboxamide, N,N-dimethyl2,2,5,5-tetramethylcyclopentene-1-carboxamide, N-phenyl

2,2,5,5-tetramethylcyclopentane-l-carboxamide, N,N-di-nbutyl-2,2,5,5-tetramethylcyclopentane-l-carboxamide, or N-(l-hydroxyl-l-phenyl-prop-2-yl)-2,2,5,5-tetramethylcyclo pentane-1-carboxamide 36. Methyl-l-hydroxy-2,2,5,5-tetramethylcyclopentane1-carboxylate; or 1-hydroxy-2,2,5,5-tetramethylcyclopentane carboxylic acid hydrazide.