Atroposelective Ir-Catalyzed C–H Borylation of Phthalazine Heterobiaryls

The atroposelective iridium-catalyzed borylation of menthyloxy-substituted phthalazine heterobiaryls with diborons is reported. Utilizing [Ir(OMe)(COD)]2/2-aminopyridine as a rarely used efficient catalyst system, the heterobiaryls were selectively borylated in the 2-position of the carbocycle, exclusively yielding only one of the atropisomers, depending on the substitution of the phthalazine with (+)-menthyl or (−)-menthyl moieties. Exemplary further functionalization of a borylated atropisomer demonstrated that nickel-catalyzed Suzuki-Miyaura cross-coupling with an aryl halide was able to provide stereoretention to a certain degree (up to 75% de).

T he position-selective and stereoselective transition metal- catalyzed C−H borylation reaction has evolved into a highly useful methodology for the introduction of functional groups, especially for arene substrates but also for alkyl C−H bonds. 1 The approach circumvents the use of functionalized substrates like aryl halides, where the halide can be transformed into the boronate by using organometallic bases (R-Li, Grignard reagents) and quenching with borates, transition metal-catalyzed processes with diborons, 2 or other functional group transformations. 3Also, a number of transition metal-free processes have been reported lately, relying on electrophilic borylation. 4Borylation reactions have been used for the synthesis of active pharmaceutical ingredients. 5Within the evolution of the methodology, recently a lot of attention is focusing on developing position-selective borylation reactions for the meta or para position of arenes 6,7 or for asymmetric borylation reactions. 8symmetric assembling of atropisomers by catalytic methodologies saw a huge advance over the last two decades. 9The synthesis of selectively borylated (hetero)biaryls using guidance by nitrogen atoms has been less developed 10 but could deliver highly interesting building blocks for the assembly of functionalized molecules for photochemical applications. 11Substitution in the 2-position of a sufficiently large arene connected to a nitrogen-containing ring as directing group can increase the configurational stability of the biaryl axis.Under ideal conditions, it can be utilized for the preparation of chiral compounds, e.g., as demonstrated for dynamic kinetic resolution via asymmetric Heck reactions 12 or the synthesis of enantiopure QUINAP derivatives by asymmetric catalysis. 13he synthesis of heterobiaryls containing other stereocenters beside the chiral axis potentially leads to resolvable diastereomers, which could be separated by, e.g., chromato-  graphic methods. 14Since we are experienced in the de novo synthesis of heterobiaryls by [2+2+2] cycloaddition, our aim was to venture into the selective postfunctionalization of the 2-position of the carbocycles by C−H borylation using chiral diborons like DB1 (see Table 1 for structure).Preliminary experiments suggested phthalazine heterocycles, utilized before as a heterobiaryl backbone in the assembly of PINAP ligands, 15 as suitable test substrates for the borylation of the heterobiaryl carbocycle in the 2-position.The test substrates containing a chiral (+)-or (−)-menthol (1) group can be easily assembled from commercially available 1,4-dichloro-phthalazine in three steps via 2a with a final Suzuki-Miyaura coupling (Scheme 1). 16The heterobiaryls (+)-3a−k and (−)-3a, b, and e were conveniently obtained by the same protocol with generally very good yields.
In the next step, we investigated the optimal conditions for the Ir-catalyzed borylation of the prepared heterobiaryls using commercially available chiral diboron DB1.Table 1 shows the results of the ligand screening for the Ir-catalyzed process at the optimized temperature of 80 °C.Utilizing 2-aminopyridine (L5) as very rare ligand for C−H borylation gave excellent 88% yield exclusively of the desired regioisomer (contrary to entries 1−4). 17It came as a genuine surprise that only one stereoisomer was found as product, suggesting a sufficient energetical difference between diastereomers on an intermediary catalytic stage.Except for ligand L6, leading to no reaction, all other ligands L7 to L9 gave good to very good yields (entries 7−9, Table 1).
After having identified that the pyridine L5 afforded the most suitable catalyst, we investigated the borylation of different substrates 3a−k to evaluate the role of the chiral menthyloxy substitutent as well as the chiral diboron DB1, its enantiomer DB2, and bis(pinacolato)diboron (DB3) in more detail.The results are displayed in Scheme 2. The most intriguing observation is the dependence of the configuration of the biaryl axis from the configuration of the menthyloxy moiety attached to the phthalazine ring while overriding any effect of the chiral diborons DB1/DB2, thus also allowing selective borylations using achiral B 2 pin 2 (DB3).
While (+)-menthyloxy substitution led to the (R a )configuration (compounds 4a, c, e, f, g, h), the introduction of a (−)-menthyloxy substituent led to the (S a )-configuration (compounds 4b, d), which was derived from structure determination in the series of heterobiaryls 5 (vide infra).The isolated yields for the heterobiaryls 4 are in general very good and range from 70 to 88% (Scheme 2, left column). 18eplacing the chiral diborons DB1 and DB2 by B 2 pin 2 (DB3) to evaluate the role of the chiral boryl group demonstrated that atroposelective borylations were also occurring in this case (5a−k, Scheme 2, right column).The dibenzothiophene 3j and phenanthrene 3k were either not reactive in the borylation (e.g., to 5l) or underwent unselective borylations. 19,20These experiments therefore established that the chiral boron moiety does not exert a direct influence on the selectivity of the C−H borylation process; however, the sterically crowded iridiumboryl complex species might pronounce the effect of the chiral menthyl auxiliar for the borylation process. 21Assignation of the absolute configuration of the biaryl axis was possible by SC-XRD of compound 5c, unambiguously confirming the (R a )-configuration of the biaryl axis (see Figure S1, Supporting Information). 22,23inally, we exemplarily investigated the further functionalization of the 2-boronate function from either the 4g or 4k-SI atropisomer by a Suzuki-Miyaura cross-coupling reaction to evaluate the configurational stability of the biaryl axis in the products 6a (Table 2).Such C−C coupling reactions with chiral boronic esters are very rare. 24We turned our attention to nickel-catalyzed cross-coupling reactions at lower reaction temperatures with 4-haloacetophenones to 6a (entries 1−4, Table 2). 25Application of Ni[P(n-Bu) 3 ] 2 (COD) as nickel precursor together with 1,4-bis(diphenylphosphino)butane (dppb) as ligand increased the yield as well as even more significantly the de value for 6a to 75% as the best case; beneficially, the aryl bromide as well as iodide reacted The Journal of Organic Chemistry identically (entries 2−4, Table 2).We investigated lower reaction temperatures to improve the selectivity and found the reaction with these catalysts to be possible even at room temperature, unfortunately without improvement of the de value (entries 5 and 6, Table 2).Shorter reaction times do not improve the stereoretention at lower yields (entries 7 and 8, Table 2).However, the developed catalytic system represents one of the very few nickel-catalyzed Suzuki-Miyaura couplings successfully working at mild reaction temperatures with Bpinane esters.In summary, we could demonstrate the ability of menthyl groups as convenient chiral auxiliaries in menthyloxysubstituted phthalazine heterobiaryls to direct the stereo-and position-selective C−H borylation with achiral and chiral diborons.The chirality of the used diborons did not play a role for the stereoselectivity of the borylation process.A rarely used in situ-generated Ir(I)-2-aminopyridine catalytic system proved to be most efficient for the process.Further functionalization of the atropisomeric 2-aryl-borylated heterobiaryls by nickelcatalyzed Suzuki-Miyaura coupling reaction with aryl halides at room temperature led to up to 75% de and 82% yield for the triaryl coupling product.

a
Isolated yields.b Reaction yielded mixture of indeterminable regioisomerically borylated heterobiaryls.c No reaction and quantitative recovery of starting material.

Table 1 .
Screening of Ligands for Directed Borylation Reaction with Substrate 3a