Pd-catalyzed cross-coupling reactions exhibiting catalyst turnover numbers (TONs) exceeding one million

Pd-catalyzed cross-coupling giving aryl–aryl, alkenyl–aryl, aryl–alkenyl, alkynyl–aryl, and alkynyl–alkenyl products exhibited ultra-high turnover numbers (TONs) of 0.7×10 7 ~0.69×10 9 by using organozincs generated in situ by treatment of the corresponding organolithiums with dry ZnBr 2 . Additionally, the hydrozirconation – Pd-catalyzed cross-coupling tandem processes via treatment of 1-alkynes with i Bu 2 AlH-ZrCp 2 Cl 2 followed by selective (≥98%) alkenyl–alkenyl coupling with either ( E )- or ( Z )-ethyl 3-bromoacrylate exhibited high TONs of 0.9×10 5 ~0.81×10 7 . Furthermore, Pd-catalyzed cross-coupling of 2-thienylzinc bromide and 1-iodo-4-nitrobenzene also showed a high TON of 0.87×10 5 .


Introduction
In any catalytic reaction, catalysts must be regenerated in their original forms.In reality, however, catalysts do become gradually decomposed and hence inactivated, resulting in finite turnover numbers (TONs hereafter).For "green" organic syntheses involving catalytic processes, catalyst TON is a critically important factor affecting the economical aspects of such processes.Several years ago, we found 1 that various representative classes of Pd-catalyzed cross-coupling of the Negishi version using Zn as the metal countercation in the organometallic reagent, would display TONs up to around 10 6 .Even if a catalyst costs a million dollars ($10 6 ) per mol the effective cost of the catalyst per production of one mol of a desired organic product is a mere $1/mol.On this basis, we opted to not pursue this matter beyond the TON level of 10 6 .Incidentally, the use of some other metal countercations under allegedly optimal conditions led to TONs up to 10 5 (observed with Al, B, In, or Zr) or in the range of 10 3 ~10 4 (observed with Mg, Mn, or Sn).
More recently, we have been informed that, in view of potential toxicity concerns, it is desirable to further improve TONs of Pd-catalyzed cross-couplings beyond the 10 6 level.On this basis and on the basis of our own scientific curiosity, we decided to pursue the TONs of representative Pd-catalyzed cross-coupling reactions beyond the previously observed range of up to around 10 6 , focusing our attention on Zn and a few other superior metals, such as Al, B, and Zr as the metal counteractions.

Results and Discussion
In order to observe high TONs in a reliable manner, we paid careful attention to avoiding false results due to contamination of the reaction system or vessel with residual catalyst, and erratic results due to any other factors.The results of the determination of TONs of the cross-coupling reactions involving aryl-, alkenyl-, or alkynylzinc bromides with aryl-or alkenyl-iodides in the presence of catalytic amounts of Pd(DPEphos)Cl2 are summarized in Table 1.For each Entry, a series of runs were followed by a blank run executed without addition of the catalyst under otherwise the same conditions.In each case, no formation of the desired product was observed.Furthermore, the catalyst solutions were prepared by a series of ten-fold dilutions with dry THF for high internal consistency among a series of experiments.
A series of reactions were initially performed at 23 °C.After observing product yields of <65% over 24 h, such reaction mixtures were heated to 70 °C, and they were further examined, confirming product yields of <65% even after 24 h at 70 °C.The TON for each case, i.e., each Entry, was calculated based on the last run exhibiting 65% yield of the desired product.All five classes of Pd-catalyzed cross-couplings shown in Table 1 exhibited unprecedentedly high TONs of the order of 10 7 ~ 10 9 .Many of the yield and TON figures represent averages of two or more runs.Moreover, each cross-coupling reaction was run at least at four catalyst concentration levels (1 ~ 10 -7 mol%), and a blank run without addition of the catalyst was also examined under otherwise the same conditions to avoid false results due to contamination.
Recently, we developed a highly selective synthesis of conjugated dienoic and trienoic esters via alkyne elementometalation-Pd-catalyzed cross-coupling tandem processes. 6(E)-Alkenylzirconium derivatives generated in situ by treating 1-alkynes with i Bu2AlH-ZrCp2Cl2 7 undergo highly stereoselective alkenyl-alkenyl coupling with either ethyl (E) 8 -or (Z) 9 -3-bromoacrylate in the presence of 1 mol% of PEPPSI-IPr (pyridine-enhanced precatalyst preparation stabilization and initiation) 10 to provide various conjugated dienoic and trienoic esters in ≥98% stereoselectivity.High TONs of 0.60~0.65×10 5 in hydrometalation-Pd(dppf)Cl2-catalyzed crosscoupling tandem reactions involving B, Al, and Zr (ZnBr2 was added after hydrometalation) were observed. 1or economic and other reasons, it is desirable to use the bromides as coupling partners.In general, however, the Pd-catalyzed cross-coupling reactions of organic bromides have been found to be more sluggish and, hence, less favorable than the corresponding reactions of iodides.To determine the efficiency of hydrozirconation-Pd-catalyzed cross-coupling tandem processes recently developed in our laboratories, 6 we examined TONs of the cross-coupling reactions between (E)-n HexCH=CHZrCp2Cl with ethyl (E)-or (Z)-3-bromoacrylate, and the results are summarized in Table 2.Both reactions provided the desired conjugated dienoic esters (≥98% stereoselectivity) with high TONs of 0.81×10 7 and 0.90×10 5 , respectively.a TON was caculated for the case where the yield of coupled product exceeds 65% with the lowest amount of PEPPSI-IPr.b The reaction was initially run at 23 ºC for 15 h, then was refluxed.c PEPPSI-IPr: In order to illustrate the high tolerance of functional groups, we also examined the TON of the cross-coupling reaction of PhZnBr(LiBr) with 4-iodobenzonitrile (Table 3, entry 1) in the presence of Pd(DPEphos)Cl2.A high TON of 0.83×10 6 was also observed in this reaction to provide the coupled product [1,1'-biphenyl]-4-carbonitrile.However, some quantities of a homocoupled biphenyl side product were observed in the reactions.
Heterobiaryls have attracted significant attention from the scientific community due to their wide range of pharmacological activities.The Pd-catalyzed cross-coupling reaction provides a very efficient method for the preparation of such compounds.However, this procedure generally suffers from high catalyst loading due to palladium catalyst poisoning by sulfur-and nitrogencontaining compounds.Negishi cross-coupling reactions using organozincs of generally higher reactivity relative to other organometallic reagents are attractive alternatives for achieving high TONs for the synthesis of heteroaryl compounds, since they typically require milder reaction conditions and shorter reaction times.PEPPSI-IPent has been proven to be an excellent catalyst for these demanding cross-coupling reactions to produce an array of biaryl and heterobiaryl compounds bearing various functional groups in excellent yields under mild reaction conditions. 11In view of the importance of heterobiaryl compounds, we also examined the TON of the cross-coupling reaction of 2-thienylzinc bromide and 1-iodo-4-nitrobenzene in the presence of PEPPSI-IPent.As shown in entry 2 of Table 3, a high TON of 0.87×10 5 was obtained for the preparation of 2-(4-nitrophenyl)thiophene.In order to demonstrate the high efficiency of PEPPSI-IPent, the cross-coupling reaction of 2-thienylzinc bromide and 1-iodo-4nitrobenzene was also performed using Pd(DPEphos)Cl2 as catalyst under similar reaction conditions.With 10 -3 mol% of Pd(DPEphos)Cl2, 2-(4-nitrophenyl)thiophene was formed in 32% yield.While 2-(4-nitrophenyl)thiophene was formed in 87% yield using 10 -3 mol% of PEPPSI-IPent.Some other solvents, such as DMF, THF/DMF (2:1), THF/NMP (2:1), and 1,4-dioxane, were also surveyed in this reaction, but there was little influence on the TON of this reaction.

Experimental Section
General.All glassware was flame-dried under vacuum, and the reactions were conducted under argon.THF and diethyl ether were dried and distilled from sodium/benzophenone under argon.ZnBr2 was flame-dried in vacuo.Pd(DPEPhos)Cl2 was prepared by the standard method. 12EPPSI-IPr, PEPPSI-IPent and 2-thienylzinc bromide solution were purchased from Aldrich and used as received.1 H and 13 C NMR spectra were recorded in CDCl3 on a Varian Inova-300 spectrometer.Chemical shifts are reported in parts per million (ppm) using CHCl3 as the reference peak.The reactions were monitored by gas chromatography (GC) using an HP 7890A GC and an HP-5 (30 m × 0.32mm, 0.25μm) capillary column, with appropriate hydrocarbons as internal standards. Tin-layer chromatography (TLC) was carried out on Merck Glass Silica Gel 60 F-254 plates. Flsh chromatographic separations were performed with 230 -400 mesh silica gel 60 and hexanes.

Table 1 .
Reaction ZnBr(LiBr) indicates that it was generated in situ by treating R1Li with dry ZnBr2.bTONwas caculated for the case where the yield of R 1 -R 2 exceeds 65% with the lowest amount of Pd(DPEphos)Cl2.

Table 2 .
High turnover numbers observed in hydrozirconation-Pd-catalyzed cross-coupling tandem reactions producing conjugated dienes

Table 3 .
High turnover numbers observed in Pd-catalyzed cross-coupling of arylzinc and heteroarylzinc reagents with aryl iodides a R 1 ZnBr(LiBr) indicates that it was generated in situ by treating R 1 Li with dry ZnBr2.bTONwas caculated for the case where the yield of R 1 -R 2 exceeds 65% with the lowest amount of catalyst.c Pd(DPEphos)Cl2 was used.d PEPPSI-IPent was used.PEPPSI-IPent: