Enantiospecific Synthesis of ortho‐Substituted 1,1‐Diarylalkanes by a 1,2‐Metalate Rearrangement/anti‐SN2′ Elimination/Rearomatizing Allylic Suzuki–Miyaura Reaction Sequence

Abstract The one‐pot sequential coupling of benzylamines, boronic esters, and aryl iodides has been investigated. In the presence of an N‐activator, the boronate complex formed from an ortho‐lithiated benzylamine and a boronic ester undergoes stereospecific 1,2‐metalate rearrangement/anti‐SN2′ elimination to form a dearomatized tertiary boronic ester. Treatment with an aryl iodide under palladium catalysis leads to rearomatizing γ‐selective allylic Suzuki–Miyaura cross‐coupling to generate 1,1‐diarylalkanes. When enantioenriched α‐substituted benzylamines are employed, the corresponding 1,1‐diarylalkanes are formed with high stereospecificity.

The 1,1-diarylalkane motif is found in many biologically relevant molecules and, as ar esult, approaches to its stereocontrolled synthesis have garnered considerable attention in recent years. [1] Aremarkably diverse array of reactivity platforms has been developed for its synthesis,i ncluding the decarbonylation of b,b-diarylpropionaldehydes, [2] the hydrogenation of 1,1-diarylalkenes, [3] and the difunctionalization of both alkyl-and aryl-substituted alkenes. [4] Amore convergent strategy is the Ni-catalyzed cross-coupling of benzylic electrophiles,t hrough both enantiospecific [5] and enantioconvergent [6] pathways.Alternatively,benzylic nucleophiles,such as boron reagents,c an be used. Fore xample,C rudden has described the stereospecific Pd-catalyzed cross-coupling of chiral secondary boronic esters with aryl iodides (Scheme 1A). [7] Accessing the required secondary benzylic boronic esters through the asymmetric rhodium-catalyzed hydroboration of styrene derivatives, [8] this method proceeds with good levels of enantio-retention to provide the desired 1,1diarylethane derivatives.W hile all these methods together provide ab road reactivity platform to access 1,1-diarylalkanes,l imitations remain with respect to substrate scope, where many methods are restricted to naphthyl-based or sterically unencumbered substrates.
We recently reported am ethod for the enantiospecific synthesis of ortho-substituted secondary benzylic boronic esters. [9] Enantioenriched a-methyl o-bromo benzylamines were transformed into dearomatized intermediate 4 through a1 ,2-metalate rearrangement/anti-S N 2' elimination reaction triggered by N-activation of arylboronate complex 2' ' (Scheme 1B). Subsequent suprafacial 1,3-borotropic shift provided the secondary a-methyl benzylic boronic esters (5)w ith excellent levels of enantiopurity.W er ecognized that the stereospecific cross-coupling of these enantioenriched benzylic boronic esters with an aryl electrophile,i nl ine with reports from Crudden, [7] would provide access to the valuable 1,1-diarylalkane motif. [10] Amore direct route to such motifs, however, would be through the interruption of the cascade sequence at the dearomatized intermediate 4,e ngaging this species in arearomatizing g-selective allylic Suzuki-Miyaura cross-coupling (Scheme 1C). [11] We envisioned that such ap athway,p assing through as ix-membered ring transition state, TS-I,would allow transfer of the chiral information in 4 and provide aroute to enantioenriched 1,1-diarylalkanes with extensive functionalization in the ortho position. Herein, we report the realization of this process,which proceeds through two consecutive stereospecific 1,3-transpositions of stereogenicity,i ncluding a1 ,2-metalate rearrangement/anti-S N 2' elimination and a syn-S E 2' g-selective Suzuki-Miyaura reaction, to provide aone pot procedure to transform enantioenriched a-branched benzylamines into enantioenriched 1,1diarylalkanes bearing considerable steric congestion in the ortho position.
We began our studies with dearomatized tertiary boronic ester 4aa,w hich was chosen because it can be isolated by column chromatography (see Supporting Information for details) and can be accessed through our previously reported 1,2-metalate rearrangement/anti-S N 2' elimination reaction. After optimization (see Supporting Information for details), cross-coupled product 6aaa was formed in 98 % 1 HNMR yield (Scheme 2A). We then undertook optimization of the one-pot procedure.D earomatized tertiary boronic ester 4aa was generated by successive treatment of ortho-bromo naphthylamine 1a with nBuLi, to form ortho-lithiated naphthylamine;c yclohexylboronic acid pinacol ester (CyBpin, 2a), giving the arylboronate complex;a nd the Nactivator,M e 2 Tr oc-Cl, to promote 1,2-metalate rearrangement/anti-S N 2' elimination. Ther eaction mixture was then treated with Ag 2 O, followed by Pd(dba) 2 ,R uPhos,a nd iodobenzene (3a)a nd heated to 75 8 8Cf or 6h.W hile some of the desired product 6aaa was observed, the yield was considerably lower (8 %) than that obtained when using isolated 4aa.Pleasingly,changing the silver salt from Ag 2 Oto Ag 2 CO 3 and optimizing the stoichiometry led to asignificant improvement in yield (90 %). Furthermore,r educing the temperature from 75 8 8Cto508 8Chad no detrimental effect on the yield, providing 6aaa in 92 %y ield as determined by 1 HNMR (Scheme 2B). Interestingly,t he 1 HNMR spectrum of the purified material contained two sets of signals in aratio of 87:13, which were shown to interconvert through variable temperature 1 HNMR experiments.W ei dentified ac oalescence temperature of 55 8 8Ca nd determined ar ate of exchange from the major to the minor species of 30.9 Hz and ar otational barrier of 17.0 kcal mol À1 . [12] Ther ate of exchange from the minor to the major species was determined to be 207.1 Hz and the rotational barrier 15.8 kcal mol À1 (see Supporting Information for details). In combination with two-dimensional EXSY/NOESY NMR experiments,these studies led us to assign the two sets of signals as rotamers, 6aaa-R A and 6aaa-R B ,w here interconversion occurs through rotation of the naphthyl-cyclohexyl C À Cb ond (Scheme 2C). [13] Furthermore,NOESY correlations support the assignment of the major rotamer as 6aaa-R A .H aving identified the two sets of signals as rotamers,w ew ere then able to confirm that 6aaa was isolated in 88 %yield. [14] With the optimized conditions in hand, we went on to investigate the scope of the three-component coupling reaction (Table 1, part A). Symmetrical cyclic secondary boronic esters gave coupled products 6aaa-6ada in excellent isolated yields.W hile cyclohexyl product 6aaa showed rotameric behaviour by 1 HNMR, cyclopentyl (6aba), cyclobutyl (6aca), and cyclopropyl (6ada)c oupled products were observed as single species.Anacyclicsecondary boronic ester also coupled smoothly,p roviding 6aea in 84 %y ield, where broadening of the methylene signal indicated restricted rotation on the 1 HNMR timescale.F or primary alkylboronic esters,t he reaction was performed at room temperature for 18 hwith improved yields,providing coupled product 6afa in 66 %yield. Interestingly,the homocoupling of the dearomatized intermediate could also be isolated in 8% yield. We attribute this product to an alternative mechanism, involving double transmetalation at apalladium(II) center,followed by reductive elimination and re-oxidation using Ag 2 CO 3 as at erminal oxidant. No coupling product was observed with sterically demanding tertiary boronic ester 2g;use of benzylamine 1b,however,led to coupled product 6bga in excellent yield (88 %). Phenylboronic ester 2halso underwent coupling to provide biaryl 6aha in 76 %y ield. In line with previous reports,t he 1,2-boron-to-carbon migration proceeded with excellent levels of retentive enantiospecificity,p roviding chiral products in high e.r. (6aia,9 5:5a nd 6bja,9 8:2) and d.r. (6aka, > 95:5 and 6ala, > 95:5). These substrates also highlight the functional group tolerance of the process,w ith tert-butyl carboxyesters,a zides,a nd TBDPS-protected alcohols tolerated.
While secondary boronic ester 5ia does undergo direct cross-coupling to provide cross-coupled product 6iaa when subjected to Cruddensc onditions (Scheme 3B), we believe that a1 ,3-borotropic shift/direct cross-coupling pathway for a-methyl benzylamine (R)-1 i is unlikely.T or ule out such ap athway,w es ubjected boronic ester 5ia to our reaction conditions,a nd observed no evidence of cross-coupled product 6iaa (Scheme 4A). [18] Furthermore,n aphthylamine 1a,w hich has been used extensively as as ubstrate in these studies,i ss table with respect to the 1,3-borotropic shift: heating 4aa in the presence of NaBPh 4 ,i nl ine with our previously reported conditions, [9] provided no evidence of the borotropic shift product (Scheme 4B). Moreover,heating 4aa in the presence of Ag 2 CO 3 ,inanalogy to our optimized allylic cross-coupling conditions,a lso showed no reactivity towards 1,3-borotropic shift. We thus propose that the transformation of a-methyl benzylamines into 1,1-diarylethane derivatives proceeds through as eries of four highly stereospecific processes:1 )astereospecific 1,2-metalate rearrangement that occurs concurrently with 2) as tereospecific anti-S N 2' elimination of the N-acylatedl eaving group to give the dearomatized intermediate, 4,followed by 3) astereospecific syn g-selective allylic transmetalation via as ix-membered transition state to give intermediate 5 and 4) astereospecific retentive reductive elimination (Scheme 4C). In this way,the chirality in the staring a-methyl benzylamine is transferred [a] Reactionswere performed using 0.3 mmol of 3,1.5 equiv of 1, 2, nBuLi (1.6 m in hexanes) and Me 2 Troc-Cl, 3equiv of Ag 2 CO 3 ,5mol %ofPd(dba) 2 , and 10 mol %ofRuPhos. See Supporting Information for exact experimental procedures.Yields refer to isolated products unless otherwise indicated. Diastereomeric ratios were determined by 1 HNMR analysis of the purified compounds. [b] Final cross-coupling step at RT for 18 h.
[c] Yield determined by 1 HNMR analysis of the crude reaction mixture using dibromomethane as internal standard.
[d] Cross-coupling step at 75 8 8Cfor 5h. through four sequential processes into the final coupled product with high stereospecificity.
In conclusion, we report anew method for the synthesis of enantioenriched 1,1-diarylethane derivatives.T hrough as eries of four stereospecific steps,e nantioenriched amethyl benzylamines are transformed into valuable optically active 1,1-diarylethanes with good stereospecificity.I nt erms of reactivity,t he key syn g-selective allylic Suzuki-Miyaura cross-coupling process appears to overcome structural limitations encountered in the traditional direct cross-coupling of certain sterically hindered secondary benzylic boronic esters. Thehighly convergent nature of this coupling process affords sterically encumbered 1,1-diarylethanes with three readily addressable points of diversification.