A Proposed Synthesis of l-Carvone from Small Molecule Precursors

 

l-Carvone is a naturally-occurring organic compound commonly found in spearmint oil extracted from mint leaves (of mentha spicata and mentha viridis ; the mentha arensis and mentha piperita varieties of mint produce peppermint oil whose principal component is l-menthone) . Spearmint oil is a complex mixture of terpene compounds , typically being comprised of 60–70% l-(–)-carvone [4R-(–)-carvone] .

The other carvone enantiomer , d-(+)-carvone [4S-(+)-carvone] , is extracted from the oils of caraway and dill seeds . Both carvone isomers are a substituted cyclohexenone , p-mentha-6,8-dien-2-one . The C4 atom is an asymmetric point center and causes carvone to exhibit optical activity :

An excellent YouTube video (MP4 , 16,083 KB , 3:34 run time) illustrates the opposite optical rotations of the two different carvone enantiomers [underlined blue hyperlinks can be clicked when online to retrieve the article cited . The requested document will open in a new window] .

l-Carvone is a clear , colorless to pale yellow , mobile oil having a pronounced and quite unique fragrant odour . While carvone is often described as having a sweet , spearmint scent , I personally find the two chemicals to be quite different in that aspect , with l-carvone having a milder , less penetrating odour than that of spearmint oil . I like to think of l-carvone as being “mellow spearmint”, lacking the sharper hydrocarbon overtones (from the minor limonene , phellandrene , and terpinene components) of spearmint :

My thanks to Mr. Amrit Kapoor of Neeru Enterprises , Rampur , India , for his gift of the 15 mL sample of l-carvone shown above . I use l-carvone , spearmint oil , and wintergreen oil (pure methyl salicylate purchased from a local pharmacy) for flavoring dry , loose tea . I greatly enjoy these delightful , fragrant , flavored teas !

Carvone boils at around 230 ºC at one atmosphere pressure , although in laboratory and industrial practice it's usually distilled in vacuo (for example , at 98–100 ºC at 10 mm ; Aldrich Chemical catalogue) to minimize oxidation and decomposition .

Both spearmint oil and l-carvone are widely used as fragrance and flavoring chemicals in many consumer products such as foods , beverages , personal care toiletries (toothpaste , mouthwash) , air freshener scents , and even in insect repellants [de Carvalho and da Fonseca (2006) ; the references are presented at the end of the text , below] . In all of these applications carvone is considered to have a very low order of human toxicity (PDF , 31 KB) . Spearmint oil is widely used in aromatherapy ; I think pure l-carvone also would be an excellent fragrance chemical for this application .

I have long been interested in the monoterpenes (since my undergraduate University days when I took a course in the chemistry of the terpenes) , and especially in carvone , which I have been using for over a decade in flavoring teas . This interest prompted my study of the various syntheses of it , resulting in the writing of this web page .

All previous syntheses of carvone have produced a racemic product . I don't know what racemic carvone nor the d-(+)- enantiomer from caraway and dill seeds smell like ; but I certainly do know what l-carvone smells like , and I'm quite fond of it ! So my objective here is to design a new enantioselective synthesis specifically of l-carvone . Half a century ago organic chemists were satisfied with the total synthesis of racemic natural products from small molecule precursors . The preferred modern approach to the asymmetric synthesis of natural products is combined with classic organic synthesis methods in the proposed new route to l-carvone discussed below . However , it might be useful to first review several modern production methods and previous total syntheses of l-carvone .

 

Commercial Production of l-Carvone

 

Carvone can be (and I suspect , mostly is) isolated by the careful fractional distillation of spearmint oil , which is produced in large quantities in the United States , with additional supplies from China and South America . Total world production of spearmint oil was about 1500 tonnes per annum (de Carvalho and da Fonseca , p. 414) back in 2006 .

Another agricultural sector , the citrus industry (again , mostly in the United States) produces large quantities of waste (eg. orange peels) from the processing of fruit into juices . This waste can be extracted with a hydrocarbon solvent such as naphtha to obtain substantial amounts of the monoterpene d-(+)-limonene , which can be converted into l-(–)-carvone via its nitrosochloride addition compound . Several of these “nitrosochloride routes” to carvone have been developed ; the most efficient one is probably that of Reitsema (1958) :

Reitsema's efficient and economical preparation of limonene nitrosochloride has been adapted for undergraduate college chemistry multi-step syntheses of l-(–)-carvone from d-(+)-limonene .

The pulp and paper industry produces large quantities of gum turpentine from the processing of deciduous (softwood) stock and logging waste , mainly by steam distillation . The principal monoterpene component of North American turpentine is a-pinene (2-pinene) , which can be converted into sobrerol by treatment with aqueous mercuric acetate (Henderson and Eastburn , 1909) . Oxidation of sobrerol (for example by chromic acid) produces 8-hydroxycarvotanacetone . However , any attempt to dehydrate this latter intermediate to carvone using an acid catalyst invariably results in the formation of the aromatic phenol , carvacrol . Booth and Klein (1957) dehydrated 8-hydroxycarvotanacetone to carvone by refluxing it with acetic or butyric anhydride :

Note that this “turpentine route” produces racemic carvone .

 

Two Syntheses of Racemic Carvone from Small Molecule Precursors

 

At least a half dozen syntheses of carvone have been reported in the chemical literature from the 1950s onward . The two most notable “total syntheses” (that is , from small molecule precursors , as opposed to modifications of a preformed para-menthane type of carbon skeleton , eg. limonene to carvone) are those of Vig and co-workers (1966) and Fleming and Paterson (1979) . Vig's carvone synthesis is outlined in the following sketch :

There are three unusual aspects to Vig's rather elaborate “building block” synthesis of carvone . His starting material , 4-methyl-2-pentenoyl chloride , is somewhat unusual (it doesn't seem to be commercially or otherwise readily available) and would require its own synthesis . Second , his Riley oxidation of intermediate 2 by selenium dioxide to produce 3 is also exceptional and unusual . And third , his transetherification of 4 to 5 and its Claisen rearrangement to 6 is very unusual and elaborate . However , Vig expressed his interest at the outset of his research report in “.....the synthesis of various terpenoids through the application of [the] Claisen rearrangement on appropriately substituted vinyl ethers ......” (p. 275) . In any case , this complicated route produced only racemic carvone and would be quite impractical for the production of any substantial amount of carvone in actual practice .

Fleming and Paterson's later carvone synthesis was much shorter and simpler than Vig's . They took advantage of a quirk discovered by other researchers in the behaviour of trimethylsilyl (TMS) enol ethers . Less substituted TMS enol ethers of cyclohexanones will be preferentially formed and isolated at very low temperatures (–78 ºC) ; these are called “kinetic” TMS enol ethers . The more thermodynamically stable , more highly substituted TMS enol ethers are formed at much high temperatures (130 ºC) . Fleming and Paterson adapted this kinetic/thermodynamic behaviour of the TMS enol ethers to their design and execution of an efficient regioselective (but not enantioselective) total synthesis of carvone starting from the common and inexpensive reagent 2-methylcyclohexanone :

The nucleophilic isopropenyl organocopper reagent (prepared in situ from the corresponding Grignard reagent in dry THF) added regioselectively to the electrophilic C3 of enone 2 , instead of to its carbonyl C1 . The strong organic oxidizer DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) was used to extract hydrogen atoms from the TMS enol ethers 1 and 4 , thereby converting them into the enones 2 and 5 (carvone) , respectively . This very clever , highly regiospecific multi-step synthesis nevertheless produced only milligram quantities of racemic carvone . In the same research report Fleming and Paterson also described their brief synthesis of piperitone (a monoterpene having a peppermint odour , used as a flavoring chemical in consumer products) , via the low temperature “kinetic” TMS enol ether of menthone , from peppermint oil . Their procedure is outlined in the sketch , piperitone-synthesis-Fleming.gif (43 KB) .

 

A Proposed Enantioselective Synthesis of l-Carvone

Part A : Four Possible Routes to 2-Methyl-1,3-heptadien-5-one

 

The following multi-step route , proposed as an enantioselective synthesis of l-carvone , can be divided into a “Part A” and a “Part B”. In Part A the key intermediate 2-methyl-1,3-heptadien-5-one would be prepared . In Part B acetaldehyde would be combined with the 2-methyl-1,3-heptadien-5-one in an asymmetric Michael addition reaction to obtain the ketoaldehyde shown above in the sketch of Vig's synthesis (between products 6 and 7) . The ketoaldehyde – now optically active – would be cyclized in situ as in Vig's procedure , this time to l-carvone .

Before starting any organic synthesis project the researcher should , of course , conduct a thorough literature survey for published reports describing the preparation of any planned intermediates that aren't commercially offered . Unfortunately , the two prime search sources used by chemists , the hardcopy Chemical Abstracts and the electronic SciFinder Scholar , are no longer available to me . Preparation of the first intermediate in this carvone synthesis , 2-methyl-1,3-heptadien-5-one , might have already been reported in the chemical literature , but I'm unaware of it , so I've suggested possible routes to it here .

The following sketches outline four possible routes to 2-methyl-1,3-heptadien-5-one . The first one would be the simplest , if it was successful . It would involve the addition of propionyl chloride , using a Friedel-Crafts Lewis acid catalyst , to isoprene (Darzen's synthesis of enones , 1910) :

Small molecule electrophiles such as HCl and HBr gases add to isoprene in a 1,4- rather than 1,2- (or even 3,4-) manner . HCl actually adds to isoprene 1,2- first , if the reaction is carried out at a low temperature (below –15 ºC) to produce 3-chloro-3-methyl-1-butene (A.J. Ultée Sr. , 1949) . This tertiary chloride rearranges to the 1,4-addition product 1-chloro-3-methyl-2-butene (“prenyl chloride”) when refluxed at its atmospheric boiling point (80 ºC at 760 mm) . Hydrogen bromide (in acetic acid solution) adds in a 1,4- manner to isoprene to provide prenyl bromide directly :

The above image was scanned from the excellent collection of classic organic syntheses compiled by Shirley (p. 51) . My thanks to the copyright owner . The prenyl halides (chloride and bromide) are versatile five-carbon synthons , and have been used in various monoterpene syntheses . They are commercially available at a modest cost (eg. from Sigma-Aldrich) .

There is no guarantee that the propionyl chloride would add to isoprene as shown in the sketch above . If it did , it would be a simple , economical preparation of 2-methyl-1,3-heptadien-5-one . Unfortunately , chemistry is often uncooperative with human aspirations . That's why three more possible routes to 2-methyl-1,3-heptadien-5-one are outlined below .

The second one resembles the first , in that the five-carbon synthon used is isopropenylacetylene (2-methyl-1-buten-3-yne) , which is somewhat similar to isoprene . At one time its chemistry was of considerable interest , as it can be hydrogenated to isoprene , a key component in the manufacture of synthetic rubber . All isoprene these days is produced by the petrochemical industry , so isopropenylacetylene has become “obsolete”and somewhat obscure . Alkynes are more reactive than alkenes , so the propionyl acylium cation will react preferentially with the acetylene bond , and in the usual Markownikov manner :

The Nenitzescu variation of the Darzens enone synthesis is recommended for the propionyl chloride addition to isopropenylacetylene . A saturated hydrocarbon such as cyclohexane added to the reaction mixture will “trade” one of its hydrogen atoms for a chlorine atom on the intermediate b-chloroketone , presumably becoming chlorocyclohexane . A non-chlorinated ketone will be obtained in the Darzens-Nenitizescu reaction , rather than a b-chloroketone . In our case the intermediate b-chlorovinyl ketone should be dechlorinated in situ to the desired product , 2-methyl-1,3-heptadien-5-one .

In the third suggested route to 2-methyl-1,3-heptadien-5-one , methallyl chloride and n-butyraldehyde (both inexpensive organic reagents) are combined to form 2-methyl-1,3-heptadiene via the Horner-Wadsworth-Emmons phosphonate modification of the Wittig olefination reaction . Allylic halides generally can combine with trialkyl phosphites to form alkyl phosphonates (the Michaelis-Arbuzov reaction) . When treated with a strong base in nonaqueous solution these alkyl phosphonates can condense with aldehydes and ketones to form olefins . In the phosphonate modification the olefin bonds have an almost exclusive trans (E) geometry :

The somewhat simpler Rathke–Nowak version of the phosphonate–aldehyde–ketone condensation could also be investigated for the preparation of the 2-methyl-1,3-heptadiene (intermediate 1) . See this sketch : Rathke-Nowak.gif (31 KB) .

Oxidation of the allylic methylene group in 2-methyl-1,3-heptadiene to a ketone carbonyl using selenium dioxide (Riley oxidation) would hopefully convert the diolefin into 2-methyl-1,3-heptadien-5-one . The reaction conditions noted in the sketch are based on the those used for the conversion of cycloheptatriene to tropone . The allylic C2 methyl , rather than the C5 methylene , might however be preferentially oxidized by the selenium dioxide (see the preparation of intermediate 3 in the sketch of Vig's synthesis above) .

The fourth suggested route to 2-methyl-1,3-heptadien-5-one is a somewhat longer variation of the Darzens synthesis of enones discussed above in the first and second routes :

The ketone carbonyl of intermediate 1 , methyl 4-keto-2-hexenoate , must be protected from attack by the Grignard reagent in the next step . The enol ether protecting group can be removed by acid-catalyzed hydrolysis in the final step in which the 2-methyl-1,3-heptadien-5-one (4) is formed .

 

Part B : The Asymmetric Synthesis of l-Carvone

 

It should be possible to add acetaldehyde to the electrophilic b-carbon of the enone bond of 2-methyl-1,3-heptadien-5-one under mildly basic catalysis (the Michael addition reaction) to produce the keto-aldehyde shown in the sketch above of Vig's synthesis (from the hydrolysis of intermediate 6) . This keto-aldehyde should be readily cyclized to the cyclic aldol , which is then dehydrated to carvone . If an asymmetric catalyst for the Michael addition step is carefully selected , the absolute stereochemistry of C4 of the new cyclohexenone ring can be set in the desired R configuration . This will result in the production of optically active l-carvone in the final step of the synthesis .

The combined Michael addition and aldol dehydration reactions to produce a substituted cyclohexenone were first used by the distinguished English organic chemist Sir Robert Robinson and co-workers in 1937 in their synthesis of octalones , which were key intermediates in the total synthesis of steroids . For this and his many other accomplishments in organic synthesis Robinson was awarded the Nobel Prize in Chemistry in 1947 . His cyclization reaction became so widely used in later years that it acquired its own name , the Robinson Ring Annulation (formerly , and incorrectly called Annelation) .

Robinson's group used a powerful base , sodium amide (sodamide) to catalyse the addition and dehydration steps in their octalone synthesis . However , much milder conditions with a secondary amine catalyst are also quite effective in the formation of cyclohexenones , as is demonstrated by the preparation of Hagemann's Ester (2) (Smith and Rouault , 1943) :

The intermediate diester enone 1 can also be completely decarboxylated under more forcing acidic hydrolysis conditions to 3-methyl-2-cyclohexen-1-one (3) . Unfortunately this fairly simple procedure cannot be readily adapted to the synthesis of carvone . It might be possible , though , to alkylate the crude diester enone 1 at C6 (sodium methoxide /methanol) with isopropyl bromide , then completely decarboxylate the isopropyl derivative to obtain racemic piperitone . See the sketch , piperitone-racemic-synthesis1.gif (64 KB) . The synthesis of racemic piperitone via the Mannich reaction and Robinson Ring Annulation is outlined in a second related sketch , piperitone-racemic-synthesis2.gif (60 KB) .

Robinson's Ring Annulation can be carried out successfully using a secondary amine as the mild basic catalyst for the Michael addition step . Two research groups , Eder , Sauer , and Wiechert (1971) and Hajos and Parrish (1974) used the natural amino acid , L-proline [S-(–)-proline , found in Nature ; the unnatural form is D-proline , or R-(+)-proline] as the Michael addition catalyst in their enantioselective Robinson Ring Annulation . Their technique has been adopted by many researchers since then , to the point where asymmetric Robinson Ring Annulations are usually referred to as the Hajos-Parrish-Eder-Sauer-Wiechert Reaction . Proline and several of its derivatives are now commonly employed as asymmetry-inducing catalysts in organic synthesis . The following sketch outlines the original Robinson Ring Annulation , its asymmetric modification by the Eder group , and the proposed enantioselective annulation of acetaldehyde and 2-methyl-1,3-heptadien-5-one :

Although Eder , Hajos , and their co-workers are given credit (and the naming honour) for the discovery and development of the asymmetric Robinson Ring Annulation , in fact Japanese organic chemists led by S. Yamada were historically (1969) the first researchers to investigate enantioselective enamine alkylations , which in one study were combined with an aldol condensation and dehydration to produce an optically-active cyclohexenone :

Yamada's second paper in effect described their enantioselective Robinson Ring Annulation :

Yamada's innovative procedure outlined above (which wasn't cited by either the Eder or Hajos groups) is especially interesting because full equivalents of their proline derivatives were used to prepare the enamine intermediates . These nucleophilic enamines were then combined with various electrophilic a,b-unsaturated olefins to complete the asymmetric synthesis of optically active cyclohexanones and cyclohexenones . In the Hajos-Parrish-Eder-Sauer-Wiechert Reaction only catalytic quantities of L-proline (or its derivatives) are used to induce asymmetry in the Michael addition step of the annulation sequence . There seems to be some debate in the literature as to the exact nature of the intermediate(s) in the Hajos-Parrish-Eder-Sauer-Wiechert Reaction . The groundbreaking work by Yamada's group back in 1969 seems to have been completely ingnored in most , if not all subsequent research in this area of asymmetric organic synthesis .

A proposed enantioselective synthesis of optically-active piperitone , based on the asymmetric enamines method pioneered by Yamada and co-workers , is presented in the sketch piperitone-asymmetric-synthesis.gif (59 KB) .

Another excellent example of an enantioselective Robinson Ring Annulation producing an optically active cyclohexenone is the synthesis of cryptone by Chen and Baran (2009) :

Cryptone is classed as a monoterpene , even though it has an incomplete p-menthane skeleton (it lacks the C7 methyl) . Stork and co-workers (1963) described a simple preparation of cryptone from the annulation of isovaleraldehydepiperidine enamine and methyl vinyl ketone , although their product was later shown to be a mixture of conjugated and non-conjugated cryptone isomers . Chen and Baran repeated Stork's preparation forty-six years later , with the addition of diphenylprolinol as the asymmetry-inducing catalyst . Their cryptone product was optically active , although they didn't specify what the absolute stereochemistry at C4 was (I've arbitrarily shown an R configuration for it in the above sketch) .

A similar asymmetric Michael addition , without a subsequent aldol condensation and dehydration to an enone , had been carried out by Chi and Gellman in 2005 :

Diphenylprolinol methyl ether was found to be a superior catalyst for asymmetric induction in the combination of aldehydes with simple , sterically-unhindered enones . With isovaleraldehyde and ethyl vinyl ketone a nearly quantitative optical yield of S enantiomer was obtained , albeit in a modest 60% chemical yield of the ketoaldehyde product .

Chi and Gellman noted ,

“In other cases such as use of b-substituted enones , which present a more demanding steric challenge , more sophisticated catalyst design will be necessary to achieve useful reactivity” (p. 4255) .

They admitted ,

“[Diphenylprolinol methyl ether] is only a poor catalyst for Michael addition of aldehydes to cyclopentenone or acyclic b-substituted enones . No Michael addition at all was detected with cyclohexenone” (p. 4255) .

Chemical yields of 60–87% were obtained with the simple methyl and ethyl vinyl ketones , which lack any b-substituents . Use of the co-catalyst , ethyl 3,4-dihydroxybenzoate , improved the yields of ketoaldehyde products when ethyl vinyl ketone was the enone substrate . In the proposed l-carvone synthesis we would have , on the one hand , a very small Michael donor aldehyde , acetaldehyde ; but , on the other hand , we would have a rather large Michael acceptor enone , 2-methyl-1,3-heptadien-5-one , having a bulky b-substituent (the isopropenyl group) . Use of diphenylprolinol methyl ether as the asymmetry-inducing catalyst in the l-carvone synthesis might thus provide a high degree of enantioselectivity in the product , but with only very low chemical yields of the optically-active carvone .

On a practical note , the diphenylprolinol methyl ether derived from natural L-proline apparently induced an S absolute configuration at C2 in Chi and Gellman's 2-isopropyl-5-ketoheptanal . Therefore , if it was used as the catalyst in the carvone synthesis , we would expect it to induce formation of 4S-(+)-carvone [caraway and dill seeds] , rather than the desired 4R-(–)-carvone [spearmint] . The unnatural D-proline , while commercially available , is quite expensive ; diphenylprolinol methyl ether would be available from it only in milligram quantities , making an asymmetric synthesis of the preferred 4R-(–)-carvone impractical .

The real challenge in this proposed synthesis route to l-carvone would thus be in the discovery or design of a suitable enantioselective catalyst for the asymmetric Michael addition of acetaldehyde to 2-methyl-1,3-heptadien-5-one . The chiral catalysts discussed in the Menthol web page could be examined in a preliminary study of the addition of acetaldehyde with several simple , readily available Michael acceptor molecules . Such acceptors could include enones and acrylate esters :

Kano and co-workers (2012) studied the addition of various aldehydes (not including acetaldehyde , though) to a selection of acrylate esters . They obtained moderate chemical yields (averaging around 70%) and excellent optical yields (averaging 94% e.e.) for their eight aldehyde substrates , using a sophisticated chiral secondary amino diol as the Michael addition catalyst . Two simple , inexpensive acrylate esters (ethyl E-crotonate and ethyl E-cinnamate) have been included in the suggested preliminary evaluation , sketched above , of chiral catalysts from the menthol study .

One of those chiral catalysts was the coordination complex of L-phenylalanine (the “natural” amino acid , GIF image , 15 KB) with anhydrous aluminum chloride , having the approximate composition [S-(–)-phenylalanine](AlCl3)3 . This complex was found to be highly effective in the polymerization of benzofuran to optically active polybenzofuran at –75 ºC . It was prepared as a clear , yellow-green solution quite simply by the combination of L-phenylalanine (1 eq.) and AlCl3 (3 eq.) in toluene at room temperature . A solution of acetaldehyde and the Michael acceptor (enone or acrylate) would then be added , dropwise (and possibly with cooling in an ice/water bath) , to the catalyst solution . The resulting product(s) would be examined in a polarimeter to see if any optical activity had been induced in them by the catalyst .

If the [S-(–)-phenylalanine](AlCl3)3 is an effective catalyst for the addition of acetaldehyde to the four Michael acceptors shown in the above sketch , it should also be satisfactory for the addition of acetaldehyde to 2-methyl-1,3-heptadien-5-one as well . In the event that the wrong carvone enantiomer is produced from the [S-(–)-phenylalanine](AlCl3)3 catalysis , the corresponding [R-(+)-phenylalanine](AlCl3)3 could be prepared for use in the addition reaction . Fortunately , D-(+)-phenylalanine (the “unnatural” amino acid) is also available commercially (eg. Sigma-Aldrich) at a moderate cost .

The synthesis of l-carvone from small precursor molecules , while conceptually simple , is more challenging than it might seem at a first glance at this small , simple enone . A successful enantioselective Robinson Ring Annulation of acetaldehyde and 2-methyl-1,3-heptadien-5-one is the key step in this proposed multi-step route . Its accomplishment would complete the total synthesis of l-carvone , a familiar yet still elusive objective in natural products chemistry .

 

References and Notes

 

de Carvalho and da Fonseca : C.C.C.R. de Carvalho and M.M.R. da Fonseca , “Carvone : Why and How Should One Bother to Produce This Terpene”, Food Chem. 95 (3) , pp. 413-422 (2006) . See also : J.A. Rogers Jr. , “Oils , Essential”, pp. 307-332 in the Kirk-Othmer Encyclopedia of Chemical Technology , 3rd ed. , M. Grayson and D. Eckroth (eds.) , vol. 16 , John Wiley , New York , 1981 . Spearmint oil and carvone are discussed on p. 328 .

monoterpenes : A.F. Thomas , “The Synthesis of Monoterpenes”, pp. 1-195 in The Total Synthesis of Natural Products , vol. 2 , J. ApSimon (ed.) , John Wiley , New York , 1973 . Vig's carvone synthesis is outlined on pp. 112-113 .

Reitsema : R.H. Reitsema , “Nitrosochloride Syntheses and Preparation of Carvone”, J. Org. Chem. 23 (12) , pp. 2038-2039 (1958) . Other related l-carvone syntheses : E.E. Royals and S.E. Horne Jr. , “Conversion of d-Limonene to l-Carvone”, J. Amer. Chem. Soc. 73 (12) , pp. 5856-5857 (1951) [outlined in the sketch carvone-synthesis.gif (42 KB)] ; C. Bordenca , R.K. Allison , and P.H. Dirstine , “l-Carvone from d-Limonene”, Ind. Eng. Chem. 43 (5) , pp. 1196-1198 (1951) ; their procedure , which was published earlier in 1951 than that of Royals and Horne , was quite similar to it , but had an overall yield of l-carvone of 35% , roughly half of the latter synthesis . Bordenca and coworkers used the very cheap urea to convert their limonene nitrosochloride into carvoxime in 99% yield , and they also successfully hydrolysed the carvoxime to carvone using 6N sulfuric acid (pH ~ 0.9) , but steam-distilling the carvone as it was formed (in 54% yield) , to prevent its tautomerization to carvacrol ; S.M. Linder and F.P. Greenspan , “Reactions of Limonene Monoxide . The Synthesis of Carvone”, J. Org. Chem. 22 (8) , pp. 949-951 (1957) ; O.S. Rothenberger , S.B. Krasnoff , and R.B. Rollins , “Conversion of (+)-Limonene to ()-Carvone : An Organic Laboratory Sequence of Local Interest”, J. Chem. Educ. 57 (10) , p. 741 (1980) .

Note : Dominguez and Leal (1963) , in their outline of student experiments using a-pinene from turpentine as the precursor to numerous monoterpenes , stated :

“The isomerization of (X) [limonene nitrosochloride] is accomplished by heating it with a mixture of urea and isopropyl alcohol or pyridine and acetone . The latter method gives carvone oxime (XI) in 9095% yield . Our students have been unable to obtain (XI) by refluxing (X) with dimethylformamide and isopropyl alcohol as described in (20) [by Reitsema]” : X.A. Dominguez and G. Leal , “a-Pinene , a Starting Material for a Sequence of Organic Experiments”, J. Chem. Educ. 40 (7) , pp. 347-348 (1963) ; exp. 11 , p. 348 .

undergraduate college chemistry multi-step syntheses : M. Chong , S. Branam , and L. Matlen , “Synthesis of l-Carvone from d-Limonene”, University of Michigan , Department of Chemistry ; no date [PDF (92 KB)] . Reitsema's simple and economical limonene nitrosochloride synthesis method was also adapted for a similar multi-step l-carvone preparation for undergraduate students by Raphael Ikan , Natural Products : A Laboratory Guide , Academic Press , New York , 1969 , and in subsequent editions of this textbook .

Henderson and Eastburn : G.G. Henderson and W.J.S. Eastburn , “The Conversion of Pinene into Sobrerol”, J. Chem. Soc. Trans. 95 , pp. 1465-1466 (1909) .

Booth and Klein : A.B. Booth and E. A. Klein , “Preparation of Carvone”, U.S. Patent 2796428 (June 18th, 1957, assigned to The Glidden Co.) [PDF (244 KB)] .

Vig and co-workers : O.P. Vig , S.D. Sharma , S. Chander , and I. Raj , “Terpenoids : Part XIII – Preparation of D,L-Carvone”, Indian J. Chem. 4 (6) , pp. 275-277 (1966) .

Fleming and Paterson : I. Fleming and I. Paterson , “A Simple Synthesis of Carvone Using Silyl Enol Ethers”, Synthesis 1979 , pp. 736-738 .

Riley oxidation : G.R. Waitkins and C.W. Clark , “Selenium Dioxide : Preparation , Properties , and Use as Oxidizing Agent”, Chem. Rev. 36 (3) , pp. 235-289 (1945) ; N. Rabjohn , “Selenium Dioxide Oxidation”, Ch. 8 , pp. 331-386 in Organic Reactions , vol. 5 , R. Adams et al. (eds.) , John Wiley , New York , 1949 ; P. Vadola , “Riley Oxidation”, Columbia University , Department of Chemistry (August 15th, 2008) [PDF (1568 KB)] ; G. Rowlands , “Oxidation of C–H Bonds , Allylic Oxidation” , p. 1 (no date) [PDF (85 KB)] . See also the tropone references below .

A.J. Ultée Sr. : A.J. Ultée Sr. , “Halogen Derivatives of Isoprene”, Rec. Trav. Chim. 68 (2) , pp. 125-137 (1949) .

Shirley : D.A. Shirley , Preparation of Organic Intermediates , John Wiley , New York , 1951 ; the prenyl bromide preparation was scanned from p. 51 . If your University or Science Library doesn't have this book , you might be able to buy a second-hand copy from ABE , the Advanced Book Exchange .

isopropenylacetylene : A.F. Thompson Jr. , N.A. Milas , and I. Rovno , “The Synthesis of Certain Unsaturated Substances from b-Ionone and Substituted Vinylacetylenes”, J. Amer. Chem. Soc. 63 (3) , pp. 752-755 (1941) ; N.A. Milas , N.S. MacDonald , and D.M. Black , “Synthesis of Products Related to Vitamin A . VIII. The Synthesis of 1-(Cyclohexen-1'-yl)-3-methyl-3-epoxybutyne-1 and Related Products”, J. Amer. Chem. Soc. 70 (5) , pp. 1829-1834 (1948) [preparation of acetylene carbinols] ; H.D. Anspon , “Preparation of Isopropenyl Acetylene”, U.S. Patent 3388181 (June 11th , 1968 , assigned to General Aniline & Film Corp.) [PDF (512 KB)] .

tropone : K.R. Dahnke and L.A. Paquette , “Inverse Electron-Demand Diels-Alder Cycloaddition of a Ketene Dithioacetal . Copper Hydride-Promoted Reduction of a Conjugated Enone . 9-Dithiolanobicyclo[3.2.2]non-6-en-2-one from Tropone”, Org. Synth. Coll. Vol. 9 , pp. 396-400 (1998) [PDF (168 KB)] . For another experimental example of a Riley oxidation using selenium dioxide (catalytically) , see J.M. Coxon , E. Dansted , and M.P. Hartshorn , “Allylic Oxidation with Hydrogen Peroxide–Selenium Dioxide : trans-Pinocarveol”, Org. Synth. Coll. Vol. 6 , pp. 946-948 (1988) [PDF (173 KB)] .

Sir Robert Robinson and co-workers : E.C. du Feu , F.J. McQuillin , and R. Robinson , “Experiments on the Synthesis of Substances Related to the Sterols . Part XIV. A Simple Synthesis of Certain Octalones and Ketotetrahydrohydrindenes Which May be of Angle-Methyl-Substituted Type . A Theory of the Biogenesis of the Sterols”, J. Chem. Soc. 1937 , pp. 53-60 .

Smith and Rouault : L.I. Smith and G.F. Rouault , “Alkylation of 3-Methyl-4-carbethoxy-2-cyclohexen-l-one (Hagemann’s Ester) and Related Substances”, J. Amer. Chem. Soc. 65 (4) , pp. 631-635 (1943) .

Eder , Sauer , and Wiechert : U. Eder , G. Sauer , and R. Wiechert , “New Type of Asymmetric Cyclization to Optically Active Steroid CD Partial Structures”, Angew. Chem. Int. Ed. Engl. 10 (7) , pp. 496-497 (1971) .

Hajos and Parrish : Z.G. Hajos and D.R. Parrish , “Asymmetric Synthesis of Bicyclic Intermediates of Natural Product Chemistry”, J. Org. Chem. 39 (12) , pp. 1615-1621 (1974) .

asymmetry-inducing catalysts : B. List , “Proline-Catalysed Asymmetric Reactions”, Tetrahedron 58 (28) , pp. 5573-5590 (2002) [PDF (500 KB)] ; E.R. Jarvo and S.J. Miller , “Amino Acids and Peptides as Asymmetric Organocatalysts”, Tetrahedron 58 (13) , pp. 2481-2495 (2002) [PDF (337 KB)] ; K. Drauz , A. Kleeman , and J. Martens, “Induction of Asymmetry by Amino Acids”, Angew. Chem. Int. Ed. Engl. 21 (8) , pp. 584-608 (1982) ; K.L. Jensen , G. Dickmeiss , H. Jiang , L. Albrecht , and K.A. Jørgensen , “The Diarylprolinol Silyl Ether System : A General Organocatalyst”, Accts. Chem. Res. 45 (2) , pp. 248-264 (2012) ; S. Sanyal , “Proline Catalysed Aldol , Mannich , and Michael Reactions : Application of Asymmetric Organocatalysis”, seminar , Michigan State University , Department of Chemistry (January 19th, 2005) [PDF (3365 KB)] ; Y. Chen , “Organocatalysts Involving Enamine and Iminium Ion Intermediates”, seminar , 34 pp. (no date) [PDF (513 KB)] ; M. Waser , “Enamine Catalysis”, Ch. 2 , pp. 7-44 in Asymmetric Organocatalysis in Natural Product Synthesis , Progress in the Chemistry of Organic Natural Products , vol. 96 , Springer-Verlag , Vienna , Austria (2012) [PDF (2097 KB)] .

S. Yamada : S. Yamada , K. Hiroi , and K. Achiwa , “Asymmetric Synthesis with Amino Acid . I. Asymmetric Induction in the Alkylation of Keto-Enamine”, Tet. Lett. 10 (48) , pp. 4233-4236 (1969) ; S. Yamada and G. Otani , “Asymmetric Synthesis with Amino Acid . II. Asymmetric Synthesis of Optically Active 4,4-Disubstituted-Cyclohexenone”, Tet. Lett. 10 (48) , pp. 4237-4240 (1969) .

Chen and Baran : K. Chen and P.S. Baran , “Total Synthesis of Eudesmane Terpenes by Site-Selective C–H Oxidations”, Nature 459 (7248) , pp. 824-828 (2009) ; their asymmetric synthesis of optically-active cryptone is outlined in Figure 2 , p. 825 , and described in detail in their Supplementary Data section , pp. 6-7 [PDF (4150 KB)] .

Stork and co-workers : G. Stork , A. Brizzolara , H. Landesman , J. Szmuszkovicz , and R. Terrell , “The Enamine Alkylation and Acylation of Carbonyl Compounds”, J. Amer. Chem. Soc. 85 (2) , pp. 207-222 (1963) ; the synthesis of racemic cryptone is described in expt. 14 on p. 219 .

was later shown to be a mixture : K.G. Lewis and J.G. Williams , “The Acid Catalysed Equilibration of 4-Alkylcyclohex-3-enones and 4-Alkylcyclohex-2-enones”, Tet. Lett. 6 (50) , pp. 4573-4577 (1965) .

Chi and Gellman : Y. Chi and S.H. Gellman , “Diphenylprolinol Methyl Ether : A Highly Enantioselective Catalyst for Michael Addition of Aldehydes to Simple Enones”, Org. Lett. 7 (19) , pp. 4253-4256 (2005) . See also : P. Kotrusz and S. Toma , “L-Proline Catalysed Michael Additions of Different Active Methylene Compounds to a-Enones in Ionic Liquid”, Arkivoc 2006 (5) , pp. 100-109 [PDF (228 KB)] .

Kano and co-workers : T. Kano , F. Shirozu , M. Akakura , and K. Maruoka , “Powerful Amino Diol Catalyst for Effecting the Direct Asymmetric Conjugate Addition of Aldehydes to Acrylates”, J. Amer. Chem. Soc. 134 (38) , pp. 16068-16073 (2012) .

optically active polybenzofuran : G. Natta , M. Farina , M. Peraldo , and G. Bressan , “Asymmetric Synthesis of Optically Active Di-isotactic Polymers from Cyclic Monomers”, Makromol. Chem. 43 (1) , pp. 68-75 (1961) ; M. Farina and G. Bressan , “Optically Active Polymers : Some New Results and Remarks on the Asymmetric Polymerization of Benzofuran”, Makromol. Chem. 61 (1) , pp. 79-89 (1963) ; G. Bressan and M. Farina , “Optically Active Polybenzofuran”, pp. 635-638 in Macromolecular Syntheses , Coll. Vol. 1 , J.A. Moore (ed.) , John Wiley , New York , 1977 .

 

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