Auto‐Tandem Catalysis: PdII‐Catalysed Dehydrogenation/Oxidative Heck Reaction of Cyclopentane‐1,3‐diones

Abstract A PdII catalyst system has been used to successfully catalyse two mechanistically distinct reactions in a one‐pot procedure: dehydrogenation of 2,2‐disubstituted cyclopentane‐1,3‐diones and the subsequent oxidative Heck coupling. This auto‐tandem catalytic reaction is applicable to both batch and continuous flow processes, with the latter being the first example of a tandem aerobic dehydrogenation/oxidative Heck in flow. In addition, a telescoped reaction involving enantioselective desymmetrisation of the all‐C quaternary centre was successfully achieved.

We herein disclose the successful development of the onepot dehydrogenation/oxidative Heck reaction of 2,2-disubstituted cyclopentane-1,3-diones 4 and its corresponding substrate scope. Furthermore, the methodology can be successfully adapted for use in ac ontinuous flow reactor,w hich constitutes the first example of an auto tandem catalytic aerobic dehydrogenation/oxidative Heck in flow.F inally,w edemonstrate that the reactionc an also be adapted fort he enantioselective desymmetrisation of the all-carbon quaternary centre in 4, throughatelescoped reaction.

Results and Discussion
We initiated our studies by investigating the Pd II -catalysed aerobic dehydrogenation of 4!1,s ince this reaction hasn ot previously been studied and would therefore require separate optimisation before the one-pot procedure 4!2 could be attempted.
Rather than Stahl's originalc onditions [(DMSO) 2 Pd(TFA) 2 in AcOH (TFA = trifluoroacetate), Scheme1C], we chose to investigate the use of 1,10-phenanthroline type ligands in DMF (Table1). The reasons for this are twofold:1 ,10phenanthroline 10 was shown to be optimal for the following oxidative Heck reaction, and would also be more suitable for adaptation to enantioselective catalysis for the followingoxidative Heck step 1!2.
With these optimised conditions in hand for the first oxidation step 4!1,w ep roceeded to investigate the one-pot procedure by carrying out the oxidation reaction at 120 8Cf or approximately 30 h, followed by addition of arylboroxine 3a (prepared by dehydrating the corresponding arylboronic acid), and allowing the oxidative Heck reaction to proceed at 70 8C( this is the optimal temperature for the separate oxidative Heck step) [10] for 43-93 h( Scheme2). Following extensive optimisation (see SupportingI nformation), the oxidative Heck product 2a wass uccessfully formed in up to 60 %y ield. Frustratingly, however,t he one-pot procedure under these conditions produced very inconsistent results, with yields ranging from 23-60 %( see Supporting Information). Whenever the yield of desired product 2aa was lower than expected, unreacted starting material 4a andi ntermediate 1a was usually present in varying amounts( see SupportingI nformation). At this point, we therefore surmised that the first oxidation step 4a to 1a was the cause of the inconsistent results. If the conversion of 4a to 1a is incomplete before the addition of 3a and cooling of the reaction to 70 8C, then no furthero xidationo f4a to 1a can take place at the lower temperature. Fortunately,aquick investigation of the oxidative Heck step showedt hat the reaction is equally effective at higher temperatures of 100 or 120 8C( Ta ble 2). Therefore, we proceeded to re-investigate the full one-potr eaction at 120 8C, in the hope that the first oxidation step will be lessi nconsistent at this higher temperature (Table 3). Unfortunately,t his still did not lead to higher yields of desired 2aa.
Another possible reason for the inconsistento xidation step 4!1 was thought to be the stabilityo ft he active Pd II catalyst at this high temperature of 120 8C: palladium black formation was occasionally observed when equal amountso fP d(OAc) 2 and ligand 10 were used (10 mol %r espectively). This problem was successfully circumvented by addition of excessl igand (vs. Pd). Pleasingly,t he addition of 20 mol %l igand 10,w hile maintaining the Pd(OAc) 2 loading at 10 mol %, resulted not only in reproducible and reliable oxidationo f4 to 2,b ut also am uch faster reactiont ime of 18 h( Scheme 3).
With much more consistent oxidation conditions in hand, the one-potp rocedure was investigated once again using the increased ligand loading (Table 4). While the oxidation of 4 to 1 was now consistently proceeding to completion (as evidenced by the absence of recovered startingm aterial 4a), the oxidative Heck reaction 4 to 2 now proved problematic. Althought he oxidative Heck reactiong oes to completionw hen carried out as as eparate step, it strugglest og ot oc ompletion under superficially similarc onditions in the one-pot reaction. Various attempts at portion-wise addition of boroxine at a range of temperatures failed to improvet he yield of 2aa (Entries 1-4, Ta ble4). Significant amounts of side products resulting from the boroxine 9,s uch as homocoupling and phenol formation,i su sually observed in the one-pot procedure. [23] Stahl proposes that the first Pd II -catalysed aerobic dehydrogenation produces hydrogen peroxide as the by-product, [17] and it is therefore likelyt hat the presence of peroxide is facilitating the unwanted side-product formation in the one-pot reaction. [23] In order to overcome this problem, the boron coupling partner was changed from arylboroxine 3 to the less reactive arylboronic esters ArBpin 9.P leasingly, this modification finally provided consistent and reproducible results (Scheme 4A). The desired product 2ab can now be formed from 4a in ao ne-pot procedure and consistent 65-67 %y ields over the two steps (increasest o7 2% under non-anhydrous conditions, see later). Another advantage of using ArBpin 9 is that it allows for a more practical procedure, as it can be added to the reaction from the outset.T his is in contrast to arylboroxine 3,w hich  Scheme3.Increasing ligand:Pd ratio significantly improves reproducibility of oxidation step. had to be added only after oxidation of 4 to 1 was complete; yields wereo therwise low due to more side-productf ormation from the arylboroxine 3.
With reproducible and optimal one-pot conditions in hand, we set out to investigate the substrate scope of the reaction. Firstly,t he aryl pinacol boronic ester scope 9 was investigated using modeld ione substrate 4a (Table 5). Unfortunately,t he optimal conditions for PhBpin 9b shown in Scheme 4A proved not to be general,a nd much lower yields were frustratingly observed when 9a and 9c were used (43 and 34 %o f2aa and 2ac,r espectively,T able 5). Increasing the catalyst and ligand loading to 15 and 30 mol %l ed to no significant improvement (45 %a nd 35 %of2aa and 2ac,r espectively).
At this point, our reasoning for this setbackw as that aryl pinacol boronic esters 9 are al ess reactivec oupling source than our originala rylboroxine or arylboronic acid coupling partners. [23][24] Under strictly anhydrous conditions, it was thought that the aryl pinacol boronic esters 9 struggle to transmetallate in the absence of base, therebyr esulting in low yields of 2aa and 2ac.T his prompted us to attempt the reaction under "wet conditions": non-anhydrous solvents and non-dried glassware, in the hope that residual water in the solventw ill be sufficient to help promote transmetallation., [23][24][25]26] Pleasingly,t hese "wet" conditions resulted in significant improvementi ny ields: from 45 to 77 %i nt he case of 3aa and 35 to 68 %i nt he case of 2ac (Table5). These non-anhydrous conditions were thus appliedt ot he subsequent substrate scope studies (Tables 5  and 6). Table 5d emonstrate that the one-pot reaction works well for Ph-and naphthyl-pinacol boronic esters (72 % 2ab and 61 % 2ad). Para-a nd meta-substitution are tolerated well (70 % 2ae and 68 % 2af), but adrop in yield to 44 %iso bserved for the ortho-substituted tolyl 2ag,p resumably due to steric factors. Both electron-donating (2ae-ag, 2aa, 2aj, 2al) and electron-withdrawing 2ac, 2ah-ai, 2ak)s ubstituents are tolerated. For as election of these pinacolb oronic esters, however,t he yields were fairly moderate using the standard conditions A( e.g. 2ac 32 %). The use of ah igher catalystl oading (15 mol %, conditions B) significantly improved the yields (e.g. 2ac 68 %) and conditions Bw ere thus adopted for the less reactive coupling partners. Although this is admittedly ar elatively high catalystloading, the fact that it is used to carry out two distinctreactions in one-pot still renders the reaction more efficient than the separate two-step procedure, which would require 10 mol %o fP d(OAc) 2 catalysti ne ach distinct step to go to completion under asimilar timescale.

Results in
Finally,c arbonyl containing substituents on the aryl ring results in low to moderate yields (47 % 2al and 18 % 2am)r egardlesso fc atalyst loading. Interestingly,t hese functional groups were tolerated well under the separate oxidative Heck Table 5. Aryl pinacolb oronic ester scope in the one-pot reaction.
[a] Non-anhydrous solvent and non-dried glassware used ("wet conditions") unless otherwise stated.I solated yields unless otherwise stated.
[a] Non-anhydrous solvent and non-dried glassware used ("wet conditions"). Isolated yields. conditions. [10] These results imply that the amide and ester functionality is sensitivet ot he first dehydrogenation step, rather than the oxidative Heck coupling itself. Once again, it is possible that the hydrogen peroxideg enerated in the first step [17] mayb er esponsible for the lower yields of 2al and 2am.
Following the successful development of the one-pot procedure in batch,w ep roceeded to investigate the reaction under continuous flow.C ontinuous flow chemistry is an attractive alternative to traditional batch chemistry as it allows for strict regulation of specific parameters (i.e. temperature, pressure, flow rate) to control reactions which are otherwise too reactive, exothermic or hazardousf or conventionalu se. [27] The increaseds urface to volume ratio is especially useful for facilitated scale-upo fg as-liquid reactions where as egmented flow can be beneficial for improving interface mixing. [27a] In our case, it should allow for more efficient O 2 facilitated catalyst turn over.F urthermore, the scaled-up reactionc an be carried out more safely and practically under flow conditions compared to batch, especially when af lammable gaseous reagent such as oxygen is employed. [28] We therefore sought to demonstrate thisb yc arrying out the first auto-tandem catalytic dehydrogenation/oxidative Heck under flow conditions. [29] The continuous flow reaction was initially investigated on 0.15 mmolo fs ubstrate 4 before it was scaled up to 1.0 mmol of substrate (Scheme 5). Initial optimisationw as carried out by varying the flow rate of both the reaction mixture( pump A) and oxygen (pump B, see Supporting Information). Af low rate of 0.4mLmin À1 and ar eactor temperature of 120 8Cw as found to be optimal for achieving full conversion to product 2ah in 3days. Pleasingly,s caling the reaction up to 1.0 mmolu nder the same conditions also resultsi nf ull conversion,f urnishing 2ah in 55 %y ield after 3days.
Finally,w ea imed to extend the one-pot procedure to the enantioselective version (Scheme 6). tBu-PyOx ligand 13 was previously used to successfully desymmetrise 1e via oxidative Heck coupling to produce 2ea in 90:10 e.r. [10] We therefore initiated our studies by investigating whether the less reactive Pd(OAc) 2 /ligand 13 catalystc ombinationc ould oxidise 1e! 4e.T he oxidation did indeed proceedt oc ompletion at 120 8C, but required 72 hu sing 13 as ligand (see Supporting Information) compared to 18 hu sing phenanthroline 10 as ligand (Scheme 3). Nevertheless, this wasd eemed promising enough to employ in the full on-pot procedure (Scheme 6).
In addition to the longer reactiont imes, af ew further modificationsw erer equired compared to the racemic procedure. Primarily, the second oxidative Heck step needs to be carried out at al ower temperature of 50 8Cf or optimal enantioselectivity,w hereas the first dehydrogenation step requires 120 8C to proceed. Secondly,i nc ontrast to the phenanthroline 10 ligand system used in the racemic protocol (Tables 5a nd 6), switching to PyOx ligand 13 results in noticeable Pd-black formationa fter dehydrogenation (i, Scheme 6A). Therefore, a second portion of Pd/ligand 13 was added together with the couplingp artner 3a during the one-pot procedure (Scheme1A). Thirdly,t he less ligating solventd imethylacetamide (DMA)was used in order to avoid issues with competitive ligationfrom DMF. [30,31] Although the one-pot reactionp roceeded to as atisfactory yield of 60 %, the enantioselectivity was moderate at 74:26 e.r. (vs. 90:10 e.r.w hen the oxidative Heck step is carriedo ut separately). [10] The moderate enantioselectivity was attributed to the presence of unligated Pd formed duringt he aerobic dehydrogenation step in the one-pot reaction. As ar esult, we proceeded to investigate the telescoped reactioni nstead,w hereby the reaction mixture is filtered through as hort plug of silica to remove any unligated Pd prior to addition of the coupling partner 3a (Scheme 6B). To our delight, the telescoped reaction provided ag ood 70 %y ield of 2ea over two steps, in 88:12 e.r., which is comparable to the 90:10 e.r.a chieved in the separate oxidative Heck procedure. [10] Scheme5. Ta

Conclusion
In conclusion, aP d II catalyst system has been used to successfully and efficiently catalyset wo mechanistically distinct reactions:d ehydrogenation of 2,2-disubstituted cyclopentane-1,3diones (4!1)a nd the subsequento xidative Heck coupling (1!2)i naone-pot procedure. Such auto-tandem catalytic reactions maximise efficiency and cut down on time, cost and waste. The developmento ft he optimal one-pot conditions was initially ac hallenging prospect, as the optimal conditions for the dehydrogenation step was not suitable for the oxidative Heck step and vice versa. Initial optimisations tudies were doggedw ith reproducibility issues, which was thought to derive from partial decomposition of the active Pd II catalyst. This problem was solved by increasing the ligand loading (vs. Pd). Secondly,t he use of arylboroxine as ac oupling partner was no longero ptimal in the one-pot protocol as it was susceptible to side-product formation,t hought to be facilitated by hydrogen peroxide formation from the aerobic oxidation step. Changing from arylboroxine 3 to the less reactive ArBpin 9 coupling partner solved these issues and allowedf or consistent and reproducible one-pot dehydrogenation/oxidative Heck reactions.
Full experimental procedures, characterisation for all new compounds and copies of 1 Ha nd 13 CNMR spectra are provided in the Supporting Information.