Alkynyl Moiety for Triggering 1,2‐Metallate Shifts: Enantiospecific sp2–sp3 Coupling of Boronic Esters with p‐Arylacetylenes

Abstract The enantiospecific coupling of secondary and tertiary boronic esters to aromatics has been investigated. Using p‐lithiated phenylacetylenes and a range of boronic esters coupling has been achieved by the addition of N‐bromosuccinimide (NBS). The alkyne functionality of the intermediate boronate complex reacts with NBS triggering the 1,2‐migration of the group on boron to carbon giving a dearomatized bromoallene intermediate. At this point elimination and rearomatization occurs with neopentyl boronic esters, giving the coupled products. However, using pinacol boronic esters, the boron moiety migrates to the adjacent carbon resulting in formation of ortho boron‐incorporated coupled products. The synthetic utility of the boron incorporated product has been demonstrated by orthogonal transformation of both the alkyne and boronic ester functionalities.

Venkataraman Ganesh, Marcin Odachowski, and Varinder K. Aggarwal* Abstract: The enantiospecific coupling of secondary and tertiary boronic esters to aromatics has been investigated. Using p-lithiated phenylacetylenes and ar ange of boronic esters coupling has been achieved by the addition of Nbromosuccinimide (NBS). The alkyne functionality of the intermediate boronate complex reacts with NBS triggering the 1,2-migration of the group on boron to carbon giving ad earomatized bromoallene intermediate.A tt his point elimination and rearomatization occurs with neopentyl boronic esters,g iving the coupled products.H owever,u sing pinacol boronic esters,t he boron moiety migrates to the adjacent carbon resulting in formation of ortho boronincorporated coupled products.T he synthetic utility of the boron incorporated product has been demonstrated by orthogonal transformation of both the alkyne and boronic ester functionalities.
Forover half acentury,cross-coupling reactions,particularly the Suzuki-Miyaura reaction, have been widely used in synthesis with applications spanning pharmaceuticals,a grochemicals and materials. [1] However,although extraordinarily useful for sp 2 -sp 2 coupling, this reaction shows rather limited scope for aliphatic boron reagents.P rimary organoboron reagents work well, but apart from afew specific examples [2] (chiral) secondary and tertiary boronic esters do not. Recently,wereported aunique approach to the stereospecific sp 2 -sp 3 coupling of boronic esters by exploiting the reaction of boronate complexes with electrophiles (Scheme 1a). [3] The coupling reaction worked well with electron rich heteroaromatics and aromatics bearing donor groups in the metaposition. However,w ithout such features no coupling occurred and bromination at the sp 3 center occurred instead (Scheme 1a). [4] In order to broaden the substrate scope to an even greater range of aromatics,w ee nvisaged the introduction of af unctional group exo to the aromatic ring that would be more reactive than the sp 3 center, and still trigger the 1,2-metallate shift. We considered the use of alkynes because they should react with electrophiles in the desired way and because of the ease with which they can be transformed into av ariety of other functional groups. [5] Furthermore,a lkynes are an important substituent in their own right owing to their prominence in natural products and as as ite for rapid and site-selective conjugation, through av ariety of Click reactions. [6] We hypothesized that treatment of the TMS-phenylacetylene derived boronate complex (C)w ith NBS should result in bromination of the alkyne [7] which would trigger 1,2metallate shift [8] leading to ad earomatized bromoallene intermediate (D)(Scheme 1b). [8] Upon reaction with anucleophile,e limination and rearomatization would result. [5] Scheme 1. General mechanism of metal-catalyzed sp 2 -sp 3 coupling of boronic esters. Here,w ed escribe the realization of this hypothesis.T o test our idea, we chose cyclohexyl pinacol boronic ester (CyBpin, 1a)a nd TMS-p-bromophenylacetylene (2a)a s standard substrates.T reatment of bromoalkyne 2a with n-BuLi in THF at À78 8 8Cf ollowed by CyBpin gave boronate complex 3a.Subsequent addition of NBS in MeOH afforded amixture of products comprising the desired coupled product 4a (40 %), ap roduct with boron incorporation in the orthoposition 4b (52 %) as well as asmall amount of 5 (6 %) along with Cy À Br formed through the direct bromination at the sp 3 carbon (Scheme 2, entry 1). At this point, we decided to optimize the reaction conditions to maximize the formation of either 4a or 4b,initially focusing on the maximally functionalized boron-incorporatedp roduct 4b.W eh ad previously observed such products when coupling electron-rich aromatics with boronic esters and found that iPrOH/MeCN gave the best ratio. [3b] We therefore carried out ab rief solvent study (entries 2-5) and again found that iPrOH/MeCN was optimal here too,giving the highest ratio,leading to a76%yield of 4b (entry 4). In THF/MeCN the reaction predominantly favored the undesired sp 3 bromination pathway,showing the need for an alcohol co-solvent (entry 3).
In order to promote the formation of the de-borinated coupled product 4a,w en eeded to promote nucleophilic attack at the boron atom and so decided to tune the steric environment around the boron center with av ariety of diol ligands.O ft he diols tested, the least hindered neopentyl glycol gave the highest selectivity for the coupled product 4a (82 %) with minimal amounts of 4b and 5 (entry 8). With increasing steric hindrance around boron, an increasing proportion of the boron incorporation product 4b was observed. Additional solvent screening showed that in TFE/ THF,t he sp 3 bromination pathway could be eliminated (entry 9).
Using the optimized conditions for creating boron-free products we explored the substrate scope of the aromatic component, employing arange of arylalkynes with astandard secondary boronic ester 6a obtained in 96:4 er using our lithiation-borylation methodology (Table 1). [9] With simple pbromophenylalkyne 2a,t he reaction furnished the expected coupled product 7a in 92 %y ield and with 100 %e nantiospecificity.W ith alkyl substituents in the ortho-( 2b)a nd meta-positions (2c)t he desired product 7b and 7c were obtained in 85 %a nd 86 %y ield, respectively.S imilarly,t he naphthylalkyne 2d also afforded the expected coupled product 7d in good yield (89 %) (minor amounts ( % 5%)o f boron incorporation was observed in all cases). Electrondonating substituents on the aromatic ring (2e and 2f) smoothly afforded the coupled products 7e and 7f in excellent yields (82 and 90 %r espectively). However,t he introduction of electron-withdrawing groups such as fluoro (2g)o rt rifluoromethoxy (2h)o nt he aromatic ring favored the direct sp 3 bromination pathway ( % 9:1) with neopentyl boronic esters,s ot he corresponding pinacol boronic esters were tested.
In comparison to pinacol, it is known that neopentyl boronic esters promote undesired S E 2r eaction at the sp 3 carbon. [10] Pleasingly,w ith 2g,a nd the pinacol boronic ester 9a the coupled product 7g was obtained in 71 %y ield. With trifluoromethoxy 2h,the desired product 7h was obtained in   am odest yield of 32 %t ogether with undesired direct bromination at the sp 3 carbon (in 2:3r atio) and minor amounts of boron incorporated products ( % 10 %). With other strongly electron withdrawing groups for example,CF 3 , CN,C O 2 t Bu bromination of the sp 3 carbon dominated over the attack on the deactivated aromatic ring. Adimethylacetal functionality 2i (representing am asked aldehyde) reacted efficiently with the corresponding neopentyl boronic ester to provide the coupled product 7i in 66 %yield. In all cases the reactions occurred with complete enantiospecificity.
We then turned our attention to the scope of secondary and tertiary neopentyl boronic esters in our coupling chemistry (Table 2). Secondary boronic esters bearing alkyl, alkenyl, cyclopropyl and silyl ether functionalities 6a-d and natural product-derived boronic ester 6e smoothly converted to the corresponding coupled product 7a, 8b-e in good yields and 100 %es. Other commonly occurring functional groups were tolerated in the boronic ester including azide (6f)a nd carbamate (6g). With tertiary neopentyl boronic esters 6h and 6i,t he reaction proceeded smoothly to furnish the coupled products 8h and 8i in 43 %a nd 79 %y ield, respectively.
We then turned to exploring the scope for the boron incorporation using pinacol boronic esters using the identified conditions (Scheme 2, entry 4). Reaction of boronic ester 9a with 2a gave the expected boron-incorporated product 10 a in 78 %y ield with 100 %e s ( Table 3). On ag ram-scale under standard reaction conditions, 10 a was obtained in 66 %yield. Similarly,with other electron-rich phenylacetylenes 2b,c and 2f, the reaction proceeded smoothly to provide the corre-sponding products 10 ab, 10 ac and 10 af in good yields.Inthe case of 2c and 2f,aregioisomeric mixture of products (10 ac1-c2 and 10 af1-f2)were observed. With other electronwithdrawing groups (e.g. CF 3 ,C N, CO 2 t Bu, Fand OCF 3 )o n the aromatic ring, in MeCN/iPrOH solvent, bromination at the sp 3 carbon was favored (> 95 %) over bromination of the deactivated phenylacetylene.
Thes cope of secondary pinacol boronic esters was also investigated (Table 3). An array of aromatic,s econdary and tertiary boronic esters bearing phenyl, alkyl, alkenyl, cyclopropyl, ester,azido,silylether,nitrile and amide [11] functional groups 9b-j all worked well furnishing the products 10 b-j in good yield (52-81 %) and 100 %e s. Natural product-derived boronic esters 9k and 9l were transformed exclusively to the boron incorporated product 10 k and 10 l in 88 %a nd 76 % yields,r espectively with complete diastereospecificity.
Them echanism that accounts for the generation of the boron-free and boron-incorporated products is shown in Scheme 3. Following the formation of boronate complex I,the reaction with NBS leads to the bromoallene intermediate II.
If the boronic ester is unhindered, subsequent attack by MeOH at boron promotes elimination leading to product Va (Path a). In contrast, if the boronic ester is hindered, nucleophilic attack is less favored, especially with iPrOH as solvent, and migration of the boron to the adjacent carbon occurs instead, relieving steric encumbrance and eliminating bromide.T his leads to carbocation intermediate IV,w hich then eliminates to the product Vb (Path b).
Theboron incorporated products provide arich source of functionality which can be chemoselectively converted into arange of diverse products (Scheme 4). Using K 2 CO 3 /MeOH the orthogonal deprotection of the TMS group was achieved providing the terminal alkyne 11 a in 87 %yield. [12] Hydration of 10 a with 20 mol %triflic acid in TFE furnished ketone 11 b in 76 %y ield. [13] Under standard CuAACc onditions, [14] 11 a was transformed to the corresponding triazole product 11 c in 85 %y ield. Oxidation of the boronic ester with H 2 O 2 /NaOH [a] Reaction conditions: p-bromophenylacetylene 2a (1.1 equiv), n-BuLi  and hydroxylamine sulfonic acid (HSA) [15] gave the desired phenol 11 d and aniline 11 e in 90 and 62 %r espectively.
Under standard Sonagashira conditions with iodobenzene, 11 a smoothly converted to the functionalized alkyne 11 f in 90 %y ield.
In summary,w eh ave successfully developed an efficient enantiospecific sp 2 -sp 3 coupling of ar ange of aromatic alkynes with ab road range of enantioenriched boronic esters.T he alkyne acts as ar eactive handle for reaction with NBS which triggers the coupling process.I mportantly,c onditions were found which either lead to the coupled product or to the coupled product bearing an ortho boronic ester.The maximally functionalized product is highly versatile as each functional group can be transformed chemoselectively making it an ideal intermediate in synthesis.