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Org. Synth. 2020, 97, 66-78
DOI: 10.15227/orgsyn.097.0066
Discussion Addendum for: Dibenzo[a,e]cyclooctene: Multigram Synthesis of a Bidentate Ligand
Günter Helmchen1*
Original Article: Org. Synth. 2012, 89, 55
Discussion
The title compound, henceforth designated dbcot, was first prepared in 1946.2 It typically served to prepare analogs of cod-complexes of transition metals. Anton and Crabtree found that dbcot is bound more tightly and is more electron with­drawing than cod in complexes of low-valent transition metal ions.3 This ob­­servation led to the first application of dbcot as a rea­gent, the Crabtree test (1983),4 which was based on the finding that dbcot is an inhibitor of homo- but not heterogeneous transition metal catalysts. Per­haps due to difficulties associated with earlier syntheses, dbcot chemistry received wider attention only after 2002, when Wudl et al.5 reported a con­ve­nient synthesis, which was some­what improved by our group.
This discussion addendum is focused on uses of dbcot and a few deri­vatives in catalysis. Useful procedures for prepa­ra­tion of these compounds are also outlined. Fun­da­mental metalorganic and coordination che­mistry of dbcot have been reviewed recent­ly (2019)6 and are here only dis­cus­sed in conjunction with cata­lysis.

Preparation of Dbcot and Dbcot Derivatives
The procedures currently in use are all based on Wudl's work. The route to dbcot, as streamlined by us, has been used by several groups without problems. Nevertheless, members of one of the groups expressed concern about the lachrymatory effect of a,a'-dibromo-o-xylene and the use of carbon tetrachloride as solvent in the bromination step.7
Wudl's work was also directed at the diyne 7 and included a ring enlar­gement of the commercially available dibenzosuberone (4) with trimethylsi­lyldiazomethane to give the ketone 5 (70%) (Scheme 1).5 This ketone was used by Chen and Hartwig for the development of a second route to dbcot by adding a Shapiro reaction via the hydazone 6 to give dbcot (1) in 83% yield (Scheme 1).8
v97p0066-2.gif
Scheme 1. A second practical route to dbcot (1)
Grützmacher et al.9 prepared a series of 5-aryl-dbcot derivatives from the ketone 5 in two simple steps (Scheme 2) and used them as ligands of transition metal catalysts. A chiral Rh-complex of 9a, obtained by resolution, gave promising results in an enantioselective Hayashi-Miyaura reaction. While the Rh-complex was stable against racemization, the free ligand (R)-9a underwent complete racemization by tub to tub interconversion within > 3 h at room temperature.
v97p0066-3.gif
Scheme 2. A route to monoaryl substituted dbcot derivatives 9
Strand et al.10 advanced the topic of asymmetric catalysis by using C2-symmetric derivatives 12 of dbcot (Scheme 3). Their synthesis commenced with the dibromide 2, which was transformed into the dione 10 according to a known procedure (Kornblum oxidation),11 which proceeded in good yield but required two equivalents of silver tosylate. The dione 10 was trans­formed into the bis-triflate 11 by treatment with Tf2O. Finally, cross coup­ling using an Fe- and a Pd-catalyst, furnished 5,11-methyl- (12a) and 5,11-phenyl-dbcot (12b), respectively. Enantiomers of both 12a and 12b could be separated by semi-preparative chiral column chromatography. The enantiomers equilibrate by tub to tub isomerization with a barrier of » 30 kcal/mol; accordingly, racemization at room temperature is slow.
The benzologue 16 (dncot) of dbcot was already prepared in 1990 in low yield.12 A convenient high yield route was developed by Wender et al. (Scheme 4).13 a,a'-Dibromo-o-xylene served as starting material; the reaction with ethynyltrimethysilane furnished the dialkyne 13 in almost quantitative yield. Subsequent deprotection to give 14 was carried out in excellent yield with 3 equivalents of silver cyanide. In the meantime, catalytic methods (10 mol% of AgNO3) have been developed14 that likely would allow simpli­fication of the deprotection step. Nickel-catalyzed [2+2+2+2]-cycloaddition to give 15 followed by oxidation furnished crystalline dncot (16) in high overall yield. Addition of bromine followed by base-promoted elimination gave the bromide 17. This allowed preparation of a variety of further de­rivatives 18 of dncot by substitution or cross coupling reactions.
v97p0066-4.gif
Scheme 3. Preparation of C2-symmetric dbcot derivatives 12
v97p0066-5.gif
Scheme 4. Preparation of dncot (15) according to Wender

Uses in Catalysis

Rhodium-Catalyzed 1,4- and 1,2-Additions of Arylboronic Acids
Interest in dbcot as a constituent of catalysts rather than as an inhibitor, cf the Crabtree test, began after Hayashi and Carreira in 2003 introduced chi­ral dienes 19 and 20, respectively, as ligands of Rh-catalysts of the Hayashi-Miyaura reaction (Figure 1) 15,16a and an Ir-catalyzed kinetic resolution allylic substitution.16b
Rh-Complexes of dienes such as cod, 19 and 20 are not very stable. This observation induced Grützmacher et al. (2005)9 to employ Rh-complexes of the dbcot derivatives 9 as catalysts. The complex (R)-21b furnished excellent yield and modest but promising enantioselectivity for the 1,4-addition of phenylboronic acid to cyclohexen-2-one (Scheme 5).
v97p0066-6.gif
Figure 1. Chiral diene ligands and complexes
v97p0066-7.gif
Scheme 5. Hayashi-Miyaura reaction
Following the rule that C2-symmetry is an advantageous property of a chiral ligand, Strand and co-workers prepared the enantiomerically pure Rh-complexes (S,S)-22a and -22b (Figure 1) from the ligands 12a and 12b, respectively.10 With these, the expected high enantioselectivities were indeed ob­tained with cyclic as well as acyclic enones and enoates (Scheme 6). In ad­dition, highly enantioselective 1,2-additions of arylboronic acids to a-keto­esters were realized by the Strand group.10
v97p0066-8.gif
Scheme 6. Use of C2-symmetric dbcot derivatives in the Hayashi-Miyaura reaction

Iridium-Catalyzed Allylic Substitutions
The Ir-catalyzed allylic substitution was introduced in 1997 and found immediate interest because of preference for the branched, chiral substitution product.17 Continuous development has led to two very robust and highly regioselective as well as enantioselective versions (type I, Scheme 7,18 and type II19)20 with many applications in the area of biologically active com­pounds.21 Both versions rely on catalysts prepared from the complex [Ir(cod)Cl]2 and a chiral phosphine. Earlier on it was not clear, whether cod was incorporated into the active catalyst. It turned out that cod is preserved in type I and lost in type II substitutions. This finding was an incentive to explore dbcot-derived catalysts in type I substitutions.
v97p0066-9.gif
Scheme 7. Ir-catalyzed enantioselective allylic substitutions of type I
There are several improvements to be gained by using dbcot-complexes in type I allylic substitutions: (a) Dbcot-Ir-complexes display enhanced ther­mal stability, because dbcot is stronger bound to IrI than cod. (b) Reactions with cod-complexes as catalysts require strict exclusion of oxygen. In stark contrast, the corresponding reactions with dbcot-complexes can be run under air and with aqueous solvents. (c) With cod, reactions often display unsatis­factory regioselectivity in case of aliphatic substituents R. With dbcot im­provement is gained because of its enhanced electron acceptor capacity.
An interesting example illustrating point (a) is due to Han et al. (Scheme 8).22 This (Tsuji) reaction involves a decarboxylative allylic substitution as the key step. With cod as an ancillary ligand, the reaction did not proceed up to a temperature of 85 °C and a reaction time of 24 h, presumably because of decomposition of the catalyst. A highly selective reaction occurred with the corresponding dbcot derived catalyst at 60 °C within 6 h.
v97p0066-10.gif
Scheme 8. Tsuji-type decarboxylative allylic etherification
Point (b), stability of the catalyst against air and water, is illustrated by Scheme 9.23 Previous attempts to accomplish an allylic hydroxylation using cod containing Ir-complexes failed in our and another laboratory.24 With dbcot as an ancillary ligand and bicarbonate as a nucleophile, the reaction could be performed with excellent results. The requisite Ir-complexes were obtained in a very convenient way as described in Scheme 10.25
v97p0066-11.gif
Scheme 9. Enantioselective allylic hydroxylation
v97p0066-12.gif
Scheme 10. One pot preparation of (allyl)Ir complexes
Tosatti et al. needed to employ similarly polar (DMSO) and aerobic con­ditions in the development of an array of drug lead-like highly polar amino acid derivatives.26,27 Use of cod as ancillary ligand furnished yields below 5%. With dbcot excellent yields of the branched (exclusively) products were obtained (Scheme 11). Peters, et al. used the similarly polar solvent dimethylformamide in combination with the complex 24 successfully for a sequential allylic substitution/aza-Cope rearrangement process.28
v97p0066-13.gif
Scheme 11. Aerobic allylic substitutions with highly polar amines in DMSO as a solvent
Improvement of regioselectivity, i. e. point (c) above, is another incentive for the replacement of cod by dbcot or dncot. Results, taken from reference 29 for cod/dbcot and reference 30 for dncot, are presented in Figure 2.29,30 It is apparent that the latter ligands induce improved regioselectivity in favor of the branched products; this is likely due to their enhanced electron withdrawing capacity in comparison to that of cod. The (R)-enantiomer of the final product in Figure 2 was required as starting material for total syntheses of the natural products (+)-crypt- and (+)-infectocaryone.31 Many further examples concerning the influence of dbcot on regioselectivity have been reported by the You group.32
v97p0066-14.gif
Figure 2. Results of reactions according to Scheme 7 using various diene ligands (ligand L2)

Miscellaneous reactions
Since 1995 Wender et al. have developed syntheses of cycloheptane derivatives via intra- and intermolecular Rh-catalyzed [5+2] cycloaddition reac­tions.33 Over the years progress with respect to reactivity and regioselec­tivity was achieved by introducing new Rh-catalysts. Currently three catalysts are being used of which one contains dncot as a ligand (Scheme 12). The crucial problems for the intermolecular reaction are regioselectivity and rate (Figure 3).13 The dncot-complex excelled particularly with respect to regioselectivity. The influence of the ligand was elucidated by dft calculations.34
v97p0066-15.gif
Figure 3. Catalysts used in [5+2] cycloaddition reactions
v97p0066-16.gif
Scheme 12. [5+2] Cycloaddition reactions according to Wender et al. (DCE: 1,2-dichlorethane, TFE: 2,2,2-trifluoroethanol)
Zhang et al. have studied polymerization of phenylacetylenes with Rh-cod as well as Rh-dbcot-complexes as catalysts (Scheme 13).35 Once more dbcot-complexes, such as 21a, excelled, displaying higher stability and acti­vity than cod-complexes due to stronger Lewis acidity caused by the high π-acidity of dbcot. Thus, on water polymerization under aerobic conditions became feasible. Facile recovery and re-use of the catalysts was possible due to their water-solubility.
v97p0066-17.gif
Scheme 13. Use of a dbcot-complex as polymerization catalyst
Finally, Grützmacher et al.36 have developed the Ru-catalyst 26, which is a hydrogenase mimic in that it is able to both catalytically split and produce H2 by stepwise release of electrons and protons (Scheme 14). Turnover num­bers up to 252 were found for the hydrogenation of vitamin K3; the quinoid moiety, rather than a double bond, was selectivity hydrogenated in the case of vitamin K2.
v97p0066-18.gif
Scheme 14. Hydrogenase mimic devised by Grützmacher et al.

References and Notes
  1. Organisch-Chemisches Institut, Universität Heidelberg, Im Neuen­hei­mer Feld 270, D-69120 Heidelberg. Email address: g.helmchen@oci.uni-heidelberg.de; ORCID ID: 0000-0003-3125-4313.
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Günter Helmchen received his chemical education at the TH Hannover (Diplom-Chemi­ker) and the ETH Zürich (Dr. sc. techn. ETH, V. Prelog). After his Habi­litation at the Univ. of Stuttgart he joined the Univ. of Würzburg in 1981 as an associate and the University of Heidelberg in 1985 as a full Professor. Currently he is a Senior Professor. His research interests are focused on stereochemical issues, in particular enantio­selective catalysis.