1,4-Cyclohexadienes--easy access to a versatile building block via transition-metal-catalysed Diels-Alder reactions.

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1,4-Cyclohexadienes—Easy Access to a Versatile Building Block via Transition-Metal-Catalysed Diels–Alder Reactions Gerhard Hilt Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, D-35043 Marburg (Germany) Fax: (+49) 6421-282-5677 E-mail: [email protected]

Received: January 16, 2014 Published online: May 30, 2014

ABSTRACT: 1,4-Cyclohexadiene derivatives are easily accessed via transition-metal cycloadditions of 1,3-dienes with alkynes. The mild reaction conditions of several transition-metal-catalysed reactions allows the incorporation of various functional groups to access functionalised 1,4cyclohexadienes. The control of the regiochemistry in the intermolecular cobalt-catalysed Diels– Alder reaction is realised utilising different ligand designs. The functionalised 1,4-cyclohexadiene derivatives are valuable building blocks in follow-up transformations. Finally, the oxidation of the 1,4-cyclohexadienes can be accomplished under mild conditions to generate the corresponding arene derivatives. DOI 10.1002/tcr.201400001 Keywords: 1,4-cyclohexadienes, catalysis, cycloaddition, Diels–Alder reactions, transition metals

The generation of 1,4-cyclohexadiene 1 and similar cyclic 1,4dienes was first described by Birch in 1944 starting from the corresponding arenes.[1] The Birch reduction utilises sodium metal in liquid ammonia as reducing agent (Scheme 1). The regiochemistry of the 1,4-cyclohexadiene can be largely controlled by the functional groups attached to the arene starting material.[2] Nevertheless, a number of functional groups, such as the nitro group, aryl halides and triple bonds, are not compatible with the rather harsh reaction conditions. As an alternative to the Birch reduction of arenes, a cycloaddition process seems reasonable. Diels–Alder reaction of a 1,3-diene and an electron-deficient alkyne as dienophile generates the desired 1,4-cyclohexadienes in a thermal, concerted [4 + 2]-cycloaddition process (Scheme 2). However, the reactivity of dienophiles with normal electron demand imposes restrictions on the dienophile, implying that only electronwithdrawing functional groups are feasible.[3–5] Some time ago, we identified an in situ generated lowvalent cobalt catalyst system to realise such a Diels–Alder-type

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cyclisation without the limitation of an electron-withdrawing group on the dienophile.[6] The original catalyst consists of CoBr2(dppe), zinc powder, and anhydrous zinc iodide. The nature of the low-valent cobalt catalyst has been established recently by a mass spectrometric investigation by Schäfer and co-workers.[7] The mass-selected and separated cobalt ions [CoBr(dppe)]+ and [Co(dppe)]+ were individually reacted with isoprene and phenylacetylene in the gas phase and exhibited significantly different affinities for these starting materials. When the [Co(dppe)]+ ion, which has a much higher affinity for the 1,3-diene and the phenylacetylene, was reacted with both starting materials, the formation of the Diels–Alder product could be observed indirectly in the gas phase by decomplexation of the Diels–Alder product from the cobalt catalyst ion. Thereby, the proposal of a stepwise mechanism for this Diels–Alder-type transformation could be underlined. In a stepwise reaction mechanism the Woodward–Hoffmann rules that apply for concerted cycloaddition processes are not relevant. Accordingly, the restrictions imposed by the

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© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim

1 , 4 - C y c l o h e x a d i e n e s a s Ve r s a t i l e B u i l d i n g B l o c k s

Scheme 1. Birch reduction of benzene.

Scheme 2. Thermal Diels-Alder reaction to 1,4-cyclohexadienes.

orbital-geometry control of the transition state are not relevant here. In fact, several functional groups are tolerated in the synthesis of the corresponding 1,4-cyclohexadiene derivatives in a regioselective fashion, yielding the 1,4-disubstituted products 3. Also, unsymmetrical starting materials, such as isoprene and phenylacetylene, gave products of type 3 as the main regioisomer. At that point of the investigation, we were

Gerhard Hilt was born in Andernach (Germany) in 1968. He studied chemistry in Bonn, where he obtained his diploma in 1992 and his Ph.D. in 1996 with Prof. E. Steckhan on indirect electrochemical regeneration of enzymatic cofactors in asymmetric biocatalysis. From 1996–98 he worked as a postdoctoral fellow with Prof. M. F. Semmelhack (Princeton, USA) on stoichiometric organometallic chemistry and from 1998–99 in the group of Prof. R. Noyori (Nagoya, Japan) on mechanistic investigations of asymmetric hydrogenation reactions. From late 1999 to 2002 he was at Ludwig-MaximiliansUniversität (Munich, Germany) for his habilitation, associated with the group of Prof. P. Knochel. In 2002 he moved to Marburg to his current position as an associate professor in organic chemistry. In 2013 he was a visiting professor at Kyoto University, Japan, associated with the group of Prof. J.-i. Yoshida. His research interests are electron-transfer-activated transition-metal complexes of cobalt and their application as catalysts in atom-economical organic transformations. Also, zinc-initiated processes for carbon–carbon bond formation are under current investigation. Another aspect of his research is the quantification of Lewis acidities and their relation to reaction rates of Lewis acid catalysed organic transformations. For further information, see the Author Profile in Angew. Chem. Int. Ed. 2009, 48, 7964, as well as the Wiley-VCH ChemistryViews online series What’s Cooking in Chemistry under the DOI 10.1002/chemv.201000018.

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interested in the synthesis of the functionalised arene derivatives such as 4 rather than the synthesis of the 1,4-cyclohexadienes. Accordingly, we used DDQ as oxidising agent to generate such arene derivatives from the dihydroaromatic 1,4-cyclohexadiene intermediate in a sequential fashion (Scheme 3). Besides oxygen-functionalised 1,3-dienes,[8] alkynyl sulfur derivatives,[9,10] amide- and imide-functionalised alkynes,[11,12] phosphorus-functionalised alkynes,[13,14] trimethylsilyl[15] modified alkynes, and boron-functionalised alkynes could also be applied successfully in the cobalt-catalysed Diels–Aldertype reaction.[16–18] Recently, cyclopropyl substituents were placed at various positions of the 1,3-diene as well as on the alkyne component,[19] and the cobalt-catalysed Diels–Alder reaction proceeded successfully without ring opening of the cyclopropyl moieties. This result indicates that an electron transfer from the low-valent cobalt catalyst central atom to the coordinated unsaturated starting materials is unlikely, as ring opening should then have been observed. In contrast to the follow-up reactions of the functionalised arene derivatives presented up to now, we did not explore possible transformations of the 1,4-cyclohexadiene derivatives to add to the vast follow-up chemistry of 1,4-cyclohexadienes described in the literature.[20,21] Selected examples of cobaltcatalysed transformations for the synthesis of functionalised products are shown in Scheme 4. In the case of the 2-silyloxy-functionalised building blocks, such as in the synthesis of 5, the dihydroaromatic product could be isolated in good yields. For such oxygenfunctionalised dihydroarenes, oxidation led to the arene derivative and during column chromatography on silica gel the silyl protecting group will be removed at least partially to generate the corresponding phenol derivative. The application of a 1-silyloxy-functionalised 1,3-diene led to the corresponding 1,4-cyclohexadiene with the silyloxy functionality at a sp3hybridised carbon. These “anti-Birch” products with oxy or silyloxy substituents at the sp3-hybridised carbon are unstable and undergo a 1,4-elimination of the alcohol or the silanol, respectively, to generate the corresponding arene products (compare Scheme 15). Sulfur-functionalised alkynes could also be applied for the synthesis of polyfunctionalised diaryl sulfides such as 6. When amides and phosphonium salts were applied, these functionalities were not accepted in the vinylic position. Nevertheless, they were well tolerated in the allylic position, as shown for the products 7 and 8, or even further away from the triple bond. In the case of the alkynyl phosphonium salts, the dihydroaromatic intermediate is a salt-like product as well, so we decided not to isolate these intermediates but to continue with a Wittig-type olefination to generate products of type 8 in a one-pot reaction sequence. In a recent application Matsubara used a low-valent nickel catalyst for the Diels–Alder reaction of electron-deficient 1,3dienes with symmetrical alkynes (Scheme 5).[22] The 1,4-


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Scheme 3. Cobalt-catalysed Diels-Alder reaction and DDQ oxidation.

Scheme 4. Cobalt-catalysed Diels-Alder reactions of functionalised starting materials.

Scheme 5. Nickel-catalysed Diels-Alder reaction and air oxidation..

cyclohexadiene derivatives were oxidised in situ to the corresponding arenes in the presence of a base (DBU) under air. Thereby, highly substituted products such as 9 could be obtained in good overall yields. The lack of regiocontrol in such transition-metal-catalysed cycloaddition reactions can be overcome when the alkyne and the 1,3-diene subunit are applied in intramolecular Diels– Alder reactions. A selected example of such a rhodiumcatalysed Diels–Alder reaction is shown in Scheme 6.[23,24] The 1,4-cyclohexadiene derivative 10 was obtained in quantitative yield as a single regio- and diastereomer. One of our most important contributions to the synthesis of 1,4-cyclohexadiene derivatives was reported in 2006.[25] The


Scheme 6. Intramolecular rhodium-catalysed Diels-Alder reaction.

modification of the ligands on the cobalt centre led us to explore an altered regioselectivity of the 1,4-cyclohexadiene derivatives formed in the Diels–Alder reaction (Scheme 7). The oxidation of these meta-substituted 1,4-cyclohexadiene

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Scheme 7. Regiodiverse and ligand controlled cobalt-catalysed Diels-Alder reaction.

Scheme 8. Meta-selective cobalt-catalysed Diels-Alder reaction.

derivatives could also be performed with DDQ to obtain the 1,3-disubstituted arene derivatives such as 11 in good overall yields. The regiocontrol of the cobalt-catalysed Diels–Alder reaction was accomplished utilising diimine or pyridine-imine ligands of type 12. For the conversion of isoprene with phenylacetylene the regioisomer 11 was generated in excellent yield and regioselectivity. The rationale for the change of regioselectivity for pyridineimine-type ligands was investigated in silico by Frenking. The results of this investigation pointed strongly towards steric factors being responsible for the dramatic change in regioselectivities.[26] Recently, Frenking also showed that electronic modifications in the 4 and 4′ positions of the pyridineimine ligands (R1 and R2, Scheme 8) had negligible effect on the regioselectivities.[27] These calculations were in very good agreement with the experiments, so further optimisation of the catalyst system to increase the regioselectivity will have to focus on steric rather than electronic modifications.

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With the pyridine-imine-type ligands the cobalt-catalysed Diels–Alder reactions of several functionalised building blocks were accomplished.[25,28] Selected examples are given in Scheme 8, including the application of sulfones (13; py-imine: R1, R2 = H) and trimethylsilyloxy groups (14). The scope of these reactions could also be expanded towards trimethylsilylfunctionalised products, such as 15 and 16.[28] The stereodivergent synthesis of the two regioisomers was accomplished in good yields and regioselectivities, and applications of such multifunctionalised building blocks have scarcely been investigated. The possibility to synthesise both regioisomers via a Diels–Alder reaction inspired us to circumvent a problem in the cyclotrimerisation of alkynes for the regioselective synthesis of multiply substituted arenes. The cobalt-catalysed cyclotrimerisation of alkynes is a powerful method to form three carbon–carbon bonds in a single synthetic operation.[29] However, the problem of the regioselective formation of a



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single product from three different alkynes in an intermolecular fashion remains unsolved (Scheme 9). Up to 37 derivatives with a 1,3,5- or a 1,2,4-substitution pattern can be formed when three simple alkynes are applied in the cyclotrimerisation reaction. In order to obtain just one of the possible derivatives, many reactions have been performed where two or even all three alkynes were reacted in an intramolecular fashion.[30] Although very impressive polycyclic products were generated, the synthetic workload was shifted towards the sometimes lengthy and tedious synthesis of the appropriate starting materials. Therefore, we envisaged that this limitation could be overcome when the three-component synthesis of arenes was performed in a one-pot reaction sequence. The formation of the three carbon–carbon bonds of the arene derivative should be separated in time, but not in space. One of the most outstanding examples for the synthesis of the 1,3,5-trisubstituted benzene derivative 19 via a metathesis/Diels–Alder approach is given in Scheme 10. The synthesis was initiated by a regioselective rutheniumcatalysed enyne metathesis for the generation of the 1,3-diene 17, which was not isolated. In the next step of the one-pot procedure, the regiodiverse cobalt-catalysed Diels–Alder reaction was applied utilising a py-imine ligand and the second alkyne, in this case trimethylsilylacetylene, so that the 1,3,5trisubstituted 1,4-cyclohexadiene intermediate 18 was generated, before the synthesis of arene 19 was accomplished upon

Scheme 9. Cobalt-catalysed cyclotrimerisation of three different alkynes.

DDQ oxidation.[31] Fortunately, both regioisomers can be generated in the cobalt-catalysed Diels–Alder reactions by applying two different ligand designs (compare Scheme 7). The regioselective formation of the meta-substituted Diels–Alder adduct was recently applied in the cobalt-catalysed formation of the dibromoterphenyl derivative 20 (Scheme 11), utilising the reaction sequence outlined in Scheme 10. The product 20 was isolated in 69% yield as a single regioisomer after recrystallisation. The sublimation of 20 under high vacuum onto a copper (111) surface led to the formation of the zigzag polymer 21 via an Ullmann-type coupling upon heating of the copper surface.[32,33] Under modified conditions the formation of cyclic products (22, hyperbenzene) was observed including 18 benzene rings in a hexagonal array (Figure 1). The Ullmanntype synthesis of 22 in solution was not successful thus far.[34] The main focus of these investigations was directed towards the incorporation of functional groups for the synthesis of the corresponding functionalised arene derivatives. However, the functionalised 1,4-cyclohexadiene derivatives bearing functional groups in either the vinylic or the allylic positions, either directly bonded to the carbocycle or exocyclic, give rise to a number of follow-up reactions. These applications will be highlighted in the next section. One of the most impressive recent applications of 1,4cyclohexadiene derivatives in modern organic synthesis was described by Studer in 2013 (Scheme 12). The conversion of the 1,4-cyclohexadiene 23 to the product 24 was accomplished via a regioselective alkylation followed by a decarboxylative palladium-catalysed cross-coupling to afford the product in 67% overall yield.[35] The authors were able to show that the functionalisation and carbon–carbon bond-formation processes at the ipso, meta and para positions were made possible by their reaction sequence. An interesting application for 1,4-cyclohexadienes generated by the cobalt-catalysed Diels–Alder reaction was reported

Scheme 10. Three-component synthesis of arenes.


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Scheme 11. Surface-assisted Ullmann-coupling of 20.

Fig. 1. STM image of 22.

by Ikariya (Scheme 13).[36] The cobalt-catalysed reactions of alkynes, such as propargylic alcohol, with isoprene were performed on up to a 1.0 mol scale to generate the 1,4cyclohexadiene intermediate 25 suitable for the formation of arene–ruthenium complexes, such as 26. The in situ redox reaction in ethanol reduces ruthenium(III) to ruthenium(II) while the 1,4-cyclohexadiene is converted to the arene now

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acting as η6-ligand. These complexes were further modified towards chiral ruthenium complexes of type 27, which were used in asymmetric transfer hydrogenation reactions with prochiral ketones. The 1,4-cyclohexadiene intermediates, such as 28, generated in a cobalt-catalysed Diels–Alder reaction of alkynes with 2-trimethylsilyloxy-1,3-butadiene, exhibit a cyclic enol ether substructure (Scheme 14).[37] Under mild acidic conditions the enol ether 28 is hydrolysed and only a single carbon–carbon double bond in the 3-position remained in 29, especially when internal alkynes were applied. On the other hand, when products of type 28 generated from a terminal alkyne were used, the trisubstituted double bonds at the 3-position migrated at least partially into conjugation with the carbonyl group. Under carefully controlled reaction conditions for the hydrolysis, rarely described non-conjugated cyclohexenone derivatives could be generated utilising this strategy. When an alkoxy-type substituent was placed at the 1-position of the 1,3-diene, this substituent ended up in the allylic position of the 1,4-cyclohexadiene derivative, as in 30 (Scheme 15). Unfortunately, these intermediates are not stable under the reaction conditions and undergo elimination of the corresponding alcohol and formation of the arene derivative of type 31.[17,38] Similar observations were made with thioethers,[17] such that these types of functionalisation of the allylic position are not compatible with the reaction sequence for the synthesis of multiply functionalised building blocks.



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Scheme 12. Studer’s 1,4-cyclohexadiene approach to polysubstituted arenes.

Scheme 13. Ikariya’s synthesis of 1,4-cyclohexadienes and their use in ruthenium chemistry.

Scheme 14. Synthesis of cyclohex-3-enones.

Scheme 15. Cobalt-catalysed synthesis of “anti-Birch”-type 1,4-cyclohexadienes.

Nevertheless, the introduction of a boron substituent is well accepted in these allylic positions, because the elimination of a borohydride species would be an endothermic and less favoured reaction. Accordingly, the application of the boronfunctionalised 1,3-diene 32 could be realised in the cobaltcatalysed Diels–Alder reaction for the synthesis of the bisallylboron intermediate 33 (Scheme 16).[39] The subsequent allylboration reaction with aldehydes led to regio- and stereoselective formation of the desired product 34 in up to 84% yield (R = 4-NO2C6H4), bearing a quaternary


carbon stereocentre as well as the chiral secondary alcohol subunit. The stereochemistry of the intermediate 33 was controlled with (R,R)-Norphos as chiral ligand, which in combination with the diastereoselective allylboration led to a single diastereomer 34 and an enantioselectivity of up to 71% ee. In a recent application of an allylic boronic ester intermediate, Hilt and Erver realised a sequential four- and even a five-component reaction sequence initiated by the formation of a multiply functionalised 1,4-cyclohexadiene derivative (Scheme 17).[40,41] The key building block for the synthesis of

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Scheme 16. Asymmetric cobalt-catalysed Diels-Alder reaction of boron-functionalised 1,3-diene 32.

Scheme 17. Five-component reaction sequence.

complex molecules such as 39 is the boron-functionalised isoprene 35. This type of reagent was first described by Brown,[42] but only recently made available by Hilt via a convenient reaction protocol.[43] The reaction sequence was initiated by a regioselective Diels–Alder reaction to generate the meta-substituted 1,4cyclohexadiene derivative 36. The monosubstituted double bond in 36 does not undergo a 1,4-hydrovinylation reaction when a CoBr2(py-imine) catalyst precursor is used. For the subsequent cobalt-catalysed hydrovinylation reaction[44] a diphosphine-based catalyst, namely the CoBr2(dppp) catalyst precursor, was added to afford 37 as the main regioisomer. The allylboron subunit of the intermediate 37 was then applied in a diastereoselective allylboration reaction with 4-pentenal to afford intermediate 38, which has a single monosubstituted double bond left. In the final step of the synthesis, product 39

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is formed in a regioselective Alder-ene reaction using phenylbut-2-yne as internal alkyne.[45] Consequently, the product 39 was generated from rather simple starting materials forming five new carbon–carbon bonds in a good overall yield of 58%. This illustrates that several cobalt-catalysed reactions can be performed sequentially for the formation of complex structures. However, a natural product of this type has not been identified thus far. The “boroprene” building block 35 was used recently for the construction of photoswitchable materials 40 via a threecomponent reaction sequence utilising various aldehydes bearing additional functional groups (Scheme 18).[46] In the present example, the phosphonate moiety in 40 was used for the immobilisation of the photoswitchable material onto silica gel. In addition, the secondary alcohol group generated in the allylboration step was used as anchor for the



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Scheme 18. Cobalt-catalysed synthesis of photoswitchable derivative 40.

Scheme 19. Ozonolysis of the symmetrical 1,4-cyclohexadiene 41.

Scheme 20. Ozonolysis of the cyclohex-3-enone for the synthesis of tricarbonyl compound 43.

immobilisation of the corresponding photoswitchable derivative on a cellulose sheet via a cyanuric ester intermediate. Although photoswitchable materials such as 40 show reversible photochemical behaviour the long-term stability of these materials needs to be improved. In the past, 1,4-cyclohexadienes were used as starting material for the synthesis of 1,3-dicarbonyl compounds.[47–49] The ozonolysis of symmetrical 1,4-cyclohexadienes, such as 41, can be used for the synthesis of two molecules of the corresponding 1,3-dicarbonyl compound, such as 42, in a single step (Scheme 19). This reaction was successfully applied in the synthesis of liponic acid.[50] On the other hand, if unsymmetrical 1,4-cyclohexadienes were to be applied, the ozonolysis would lead to two different 1,3-dicarbonyl compounds by degradation of the cyclohexadiene moiety. The separation of these two products would be problematic. To circumvent the scission of the carbon skeleton, the products of the cobalt-catalysed Diels–Alder reaction using 2-trimethylsilyloxy-1,3-butadiene were investigated.


The thereby generated 1,4-cyclohexadiene intermediates can be treated with acid and ozonolysis led to ring opening rather than scission of the carbon backbone. Accordingly, 1,3,6tricarbonyl derivatives, such as 43, were generated in good yields in a short reaction sequence (Scheme 20).[51] The synthesis of more complex polycarbonyl derivatives utilising this strategy is currently under investigation and unprecedented polycarbonyl compounds such as 44 could be generated in a short and concise reaction sequence utilising cobalt-catalysed Diels–Alder and hydrovinylation reactions for the construction of the carbon skeleton (Scheme 21). In conclusion, the transition-metal-catalysed synthesis of 1,4-cyclohexadienes has been established in recent years via the Diels–Alder reaction of 1,3-dienes with alkynes. The generation of the corresponding arene derivatives upon oxidation under mild conditions represents a simple way to synthesise functionalised building blocks of this type. In particular, the application of cobalt catalysts allows the incorporation of a large number of functional groups. Of even greater interest are

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Scheme 21. Three-component synthesis of pentacarbonyl product 44.

the various functionalised 1,4-cyclohexadienes that can be generated in a stereodivergent fashion. These building blocks allow an increasing number of follow-up transformations. As we and others have been able to show, these unprecedented building blocks can be used in sequential multicomponent reactions, as well as for the synthesis of new ligands for transition metals, photoswitchable molecules, and polycarbonyl derivatives. From a personal perspective, I would expect that 1,4cyclohexadienes will be used in the synthesis of increasingly complex molecules in the future, based on the broad possibilities for installing various functional groups in the vinylic as well as the allylic position around the 1,4-cyclohexadiene subunit.

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