Transition Metal Catalyst‐Free, Base‐Promoted 1,2‐Additions of Polyfluorophenylboronates to Aldehydes and Ketones

Abstract A novel protocol for the transition metal‐free 1,2‐addition of polyfluoroaryl boronate esters to aldehydes and ketones is reported, which provides secondary alcohols, tertiary alcohols, and ketones. Control experiments and DFT calculations indicate that both the ortho‐F substituents on the polyfluorophenyl boronates and the counterion K+ in the carbonate base are critical. The distinguishing features of this procedure include the employment of commercially available starting materials and the broad scope of the reaction with a wide variety of carbonyl compounds giving moderate to excellent yields. Intriguing structural features involving O−H⋅⋅⋅O and O−H⋅⋅⋅N hydrogen bonding, as well as arene‐perfluoroarene interactions, in this series of racemic polyfluoroaryl carbinols have also been addressed.


Introduction
Over the past few decades,the transition-metal-catalyzed 1,2-addition of organometallic reagents to the C = Ofunctionality of aldehydes and ketones has developed as au seful method for the synthesis of substituted secondary and tertiary alcohols. [1] Numerous reagents have been used for these reactions,i ncluding organomagnesium, [2] organozinc, [1,3] organolithium, [4] organosilane, [5] organostannane, [6] organocerium, [7] and organoboron compounds. [8] In particular,o rganoboronate reagents offer significant advantages such as air and moisture stability,l ow toxicity,g ood functional group tolerance,a nd availability. [8] In 1998, Miyaura and co-workers [9] first reported the addition of arylboronic acids to aldehydes using aR hc atalyst. In subsequent studies,o ther rhodium, [10] palladium, [11] platinum, [12] nickel, [13] copper, [14] iron, [15] cobalt, [16] and ruthenium [17] complexes have been developed as precatalysts for such reactions.H owever,t ransition metals can be expensive,t oxic, and difficult to remove completely from the corresponding product. At ransition metal-free strategy would be highly desirable for these useful transformations.T he reaction products for the addition of arylboronic acids to ketones,a fter hydrolysis,a re tertiary alcohols,which are important building blocks for the synthesis of pharmaceuticals,a grochemical compounds,a nd natural products. [18] However,t he nucleophilic addition of organometallic reagents to ketones can be challenging due to the inherent steric congestion around the carbonyl group,f requently resulting in the generation of products arising from side reactions such as reduction and aldol condensation. [19] Therefore,t he development of an efficient, general, and convenient protocol for the synthesis of tertiary alcohols is of considerable interest.
Moreover,a ni deal strategy to synthesize ketones,i mportant and ubiquitous structural motifs, [20] lies in the transition metal-catalyzed replacement of an aldehydes C(O)-H group with acarbon electrophile. [21] Recently,Zheng and co-workers demonstrated the direct functionalization of aldehyde CÀH bonds with aryl halides,using aprecious metal palladium catalyst, which has proven to be aviable method to generate the corresponding ketone products. [22] Polyfluoroarenes have gained extensive attention due to their important role in pharmaceutical, agrochemical, and advanced materials. [23] Thus,identifying practical and efficient concepts for the introduction of fluorine or fluorinated building blocks is highly desirable.Several studies have been reported regarding the polyfluorophenylation of aldehydes. Fore xample,i n1 999, Knochel and co-workers [24] used fluorinated aryl bromides to perform pentafluorophenylation of aldehydes (Scheme 1a). More recently,L am and coworkers [25] used ac opper catalyst (Scheme 1b)a nd Gu and co-workers [26] (Scheme 1b)u sed an N-heterocyclic carbene (NHC) organocatalyst to obtain fluorinated aryl carbinols using polyfluorophenyl trimethylsilane as an ucleophile for the addition to aldehydes.I n2 015, Huang and co-workers [27] (Scheme 1c)reported aMg-mediated polyfluoroaryl addition to aldehydes.Although some advancements in this field have been reported, these methods suffer from the requirement for highly flammable Grignard reagents,t ransition metals or NHC catalysts.Moreover,methods reported by Lam and coworkers and Gu and co-workers are limited to pentafluorophenyl trimethylsilane or 1,4-bis (trimethylsilyl) tetrafluorobenzene as substrates.
Recently,w er eported efficient methods to generate fluorinated arylboronic acid pinacol esters (Ar F -Bpin) via C-F borylation of fluoroarenes using NHC-ligated Ni complex [28a,b] and C-Cl borylation of Ar F -Cl using Pd catalyst under base free condition. [28c] Likewise,w er eported optimized conditions for the Suzuki-Miyaura cross-coupling reaction of Ar F -Bpin compounds with ArX (X = Br,I )u sing ac ombination of CuI and 1,10-phenanthroline as ac atalyst precursor. [28d] Furthermore,w er eported the palladium-catalyzed homocoupling of fluorinated arylboronates, [28e] and the copper-catalyzed oxidative cross-coupling of electron-deficient polyfluorophenyl boronate esters with terminal alkynes. [28f] We report herein the transition metal-free polyfluorophenylation of ketones and aldehydes with fluorinated aryl boronates,which provides aconvenient and novel strategy for the synthesis of alcohols and ketones.

Results and Discussion
Addition of arylboronic acids to aldehydes using transition metal catalysts has been well developed. We expected that the use of more Lewis acidic pentafluorophenyl-Bpin with abase would generate anucleophilic intermediate in the absence of at ransition metal. To verify our hypothesis,w e initially examined the reaction of pentafluorophenyl-Bpin (1a)and benzaldehyde (2a)asamodel reaction. As shown in Table 1, secondary alcohol 3a was observed as the addition product after hydrolysis when the mixture of 1a and 2a was heated in the presence of KOMe as the base (Table 1, entry 1). Encouraged by this first result, we screened the reaction parameters,i ncluding the base and the solvent, to improve the performance of the reaction. Theemployment of K 2 CO 3 as the base dramatically increased the yield to 92 % (  16,17). However,u nder anhydrous conditions,t he transition metal-free Scheme 1. Approachest oaccess polyfluoroaryl carbinolsv ia the addition to aldehydes. polyfluorophenylation of benzaldehyde with pentafluorophenyl-Bpin is feasible and leads to high yields of the desired product.
Using these optimized conditions,weevaluated the scope and the limitations of this reaction. As shown in Table 2, as eries of aldehydes bearing electron-withdrawing or -donating substituents at the para-, meta-, or ortho-position all worked well with pentafluorophenyl-Bpin to give the desired products (3b-3k). Notably,f or reactions employing aldehydes bearing electron-donating groups,i ncreasing the reaction temperature to 80 8 8Cf or 48 hours was required to generate the corresponding products in acceptable yields.I t should be noted that reactions using 4-(diethoxymethyl)benzaldehyde resulted in cleavage of the diethoxymethyl group yielding 3l.Furthermore,this methodology could be successfully extended to more complex aldehydes,s uch as those incorporating naphthyl and pyridyl groups (3m and 3n). The structures of compounds 3f, 3l, 3m and 3n were unambiguously confirmed via single crystal X-ray analysis (vide infra).
After ab road range of aromatic aldehydes were examined, reactions with aliphatic aldehydes were investigated using the optimized conditions.G ratifyingly,a ll reactions proceeded smoothly to afford the corresponding products (3o-3q). Importantly,a ldehydes containing ester groups,w hich are well-known to be sensitive towards Grignard reagents,a lso afforded the desired alcohols in excellent yield (3r).
We then briefly investigated the scope using simple ketones (Table 3). When reactions were performed at 120 8 8C and for prolonged reaction times,the corresponding products were provided in moderate yields (3s-3u). Modest reaction yields were obtained when sterically hindered benzophenone and (2-fluorophenyl)(phenyl)methanone were used (3v-3w). Importantly,c yclohexanone proceeded to give the desired products in good yield (3x).
To gain further insight into the aforementioned reactions, several mechanistic studies were conducted. Ther eaction of 2a with pentafluorobenzene 5 under standard conditions was  examined, yet 3a was not formed in any detectable amounts (Scheme 2a), indicating that the C-Bpin moiety is essential and deprotonation of the fluoroarene or nucleophilic attack at the fluoroarene by the base is not ap lausible pathway. Interestingly,f or the standard reaction between 1a and 2a, the yield dropped dramatically if 18-crown-6 ether and K 2 CO 3 were added (Scheme 2b). This experimental result indicates that the presence of the potassium ion plays acrucial role for the outcome of the reaction. Furthermore,i ft he reaction of 1a and 2a was performed in the presence of only ac atalytic amount of K 2 CO 3 (20 mol %) (Scheme 2c), reaction rates were reduced, and aw eek was required to produce 3a in good, isolated yield. This finding again indicates that the potassium ion (or the base) plays an important role in the reaction. Substituting ortho-fluorines by ortho-chlorines,u sing either C 6 Cl 5 Bpin or 2,6-dichlorophenyl-1-Bpin as substrates,d id not yield any product as shown by in situ GCMS studies.Likewise,2,3,4-trifluorophenylBpin and 3,4,5-trifluor-ophenylBpin substrates with only one or no ortho-fluorine substituent also led to no detectable product formation. The presence of an ortho-methoxy group on the aldehyde, however, did not inhibit the reaction.
Based on previous studies [28,29] and experimental observations,amechanism for the 1,2-addition of polyfluorophenylboronates to aryl aldehydes in the presence of K 2 CO 3 as base is proposed, as shown in Scheme 3. K 2 CO 3 interacts with the Lewis-acidic Bpin moiety of substrate 1 to generate base adduct A,w hich weakens the carbon-boron bond and ultimately cleaves the BÀCb ond along with attachment of apotassium cation to the aryl group.The resulting Ar F À anion adduct B undergoes nucleophilic attack at the aldehyde carbon atom of substrate 2 to generate methanolate C.T he methanolate oxygen atom then attacks the electrophilic Bpin group to obtain compound D.T ransfer of K 2 CO 3 from intermediate D to the boron atom of the more Lewis-acidic polyfluorophenyl-Bpin 1 finally closes the cycle and regenerates complex A.T hus,t he primary reaction product is the O-borylated addition product E,w hich was detected by HRMS and NMR spectroscopy for the perfluorinated derivative (Supporting Information, section VIII).
To corroborate this mechanism, adetailed DFT study was performed on the model 1,2-addition of 1a to 2a,t he results  of which are shown in Figure 1. In the initial step,K 2 CO 3 coordinates to the Bpin moiety of 1a and gives rise to the pentafluorophenyl-Bpin-basec omplex 6 with free energy decreasing by 27.2 kcal mol À1 .T he energy of compound 6 is set as the zero point of the energy profile.T he pentafluorobenzene anion (Ar F À )adduct 8 is formed endothermically by cleavage of the B-C(Ar F )bond via transition state 7-ts with an energy barrier of 26.4 kcal mol À1 .I nt he optimized structures of 7-ts,K + cations coordinate to C, Oa nd Fatoms,w hereas there is only K-O coordination in compound 6.S ubsequent cleavage of the B-C(Ar F )b ond can be facilitated by this pathway.T he separated carbonate adduct and Ar F À group in adduct 8 are connected and stabilized by K + cations. Nucleophilic attack of Ar F À at the aldehyde carbon atom via transition state 10-ts occurs to achieve the coupling intermediate 11 with an energy of 17.6 kcal mol À1 .T his low activation energy barrier can be attributed to the coordination of K + to the oxygen atom of the aldehyde,thus enhancing the electrophilicity of the aldehyde carbon atom. Subsequently,t he methanolate oxygen atom attacks the Lewis-acidic boron atom to give the corresponding compound 13 irreversibly via transition state 12-ts.T he overall energy barrier for this step is 16.2 kcal mol À1 .F inally,K 2 CO 3 in compound 13 coordinates to the boron of substrate 1a via transition state 14-ts,f ollowed by cleavage of aB À Ob ond to give 16-ts and eventually 17,regenerating the active species 6.Ass hown in Figure 1, the energy barriers for these two steps are very low, indicating that intermediate 13 transforms to product 17 swiftly.T he step from pentafluorophenyl-Bpin-base compound 6 to product 17 is calculated to be exergonic by 14.3 kcal mol À1 .T he base-assisted cleavage of Bpin and pentafluorophenyl (Ar F )i sc alculated to be the rate determining step (RDS) with af ree energy of activation of 26.4 kcal mol À1 .
As shown in Figure 1, the cation K + bonds with one or two Fatoms in these intermediates and transition states,s uggesting that the fluoride substituents possibly play an important role in the 1,2-addition of polyfluorophenylboronates to aryl aldehydes.T herefore,w ec alculated the activation free energies of the RDS using polyfluorophenylboronates with different numbers and positions of fluorine substituents as the substrate.T he results given in Figure 2c learly show that the energy barrier rises with ar eduction in the number of F substituents.T he position of the fluorine atoms also affects the energy barrier, and ortho fluorine has astronger effect on the barrier than Fsubstituents at other positions.T he barrier for 24,with an ortho-F substituent, is higher than that of 22 by 2.6 kcal mol À1 ,w hereas that of 26 with a para-F substituent rises to 39.0 kcal mol À1 .I nf act, no reaction was observed under these conditions when 26 was used as the substrate, which is consistent with our calculated results.W ec onclude that the ortho-F substituent is vital in this reaction for interaction with K + along the reaction pathway,and that other Fsubstituents also influence the reactivity for the 1,2-addition of polyfluorophenylboronates to aryl aldehydes via their electron-withdrawing effect. Thus,s tronger electron-withdrawing groups located at the para or meta carbons of polyfluorophenylboronates may promote this reaction.
To ascertain the role of the K + cation in these reactions, part of the free energy profile without the cation was also

Chemie
Research Articles calculated at the same level of theory,a nd the results are given in Figure 3. Compared with the energy profile in Figure 1, in the absence of K + ,the process of the methanolate oxygen anion 33 attack at the Lewis-acidic boron in 30 becomes improbable,w ith an activation barrier of 41.4 kcal mol À1 ,a lthough the initial cleavage of Bpin and pentafluorophenyl (Ar F )s tep has al ower free energy of activation. Upon addition of 18-crown-6 to the reaction, the yields drop dramatically.A sacounterion, K + clearly regulates the nucleophilicity of CO 3 2À ,a nd promotes the reactivity by interaction with oxygen or fluorine atoms.O ur DFT calculations indicate that both the ortho-F substituents on the polyfluorophenylboronates and the counterion K + are essen-tial for the 1,2-addition of polyfluorophenylboronates to aryl aldehydes.
Thes tructures of 3f, 3l, 3m, 3n,a nd 4d were unambiguously confirmed by single crystal X-ray diffraction. While the molecular structures are chiral (Figure 4), all the compounds represent racemic mixtures.D ue to the presence of OH groups,t he arrangement of the molecules in the crystal structures of all compounds is primarily determined by OÀ H···O or OÀH···N hydrogen bonding (Supporting Information, Table S2). Thep resence of p···p stacking interactions between pentafluorophenyl and bromophenyl or naphthyl moieties (3f and 3m), respectively,i sa lso observed in these examples ( Figure 5, Table S3). Such an attractive interaction

Chemie
Research Articles between arenes and perfluorinated arenes results from the different electronegativities of the hydrogen and fluorine atoms with respect to the carbon atoms of the aromatic rings and, hence,from opposite multipole moments of the aromatic groups.I ti sc alled the arene-perfluoroarene interaction and can be applied as as upramolecular synthon in crystal engineering. [30] This was previously confirmed by Marder and co-workers,who have shown that this type of interaction leads to the formation of highly ordered p-stacks of alternating arene and perfluoroarene molecules in co-crystals of arenes and perfluoroarenes. [30d,31] In the crystal structures of compounds 3f and 3m,t he combination of both O À H···O hydrogen bonding and areneperfluoroarene interaction leads to the intriguing formation of [O À H···] 4 hydrogen-bonded cyclic tetramers with graph set R 4 4 (8) ( Figure 5, Table S2). [32] Them olecules of the tetramer interact via arene-perfluoroarene p···p stacking between the bromophenyl or naphthyl and pentafluorophenyl moieties on the outside of the cyclic [OÀH···] 4 ring. Thei nterplanar separations (3.281(7)-3.687 (14) )are typical for p···p stacking interactions [30,31] and the angles between the interacting planes are 4.96(19)-16.8(3)8 8 (Table S3). In the higher symmetry compound 3m (space group P2 1 /c with Z' = 2, where Z' denotes the number of molecules in the asymmetric unit), arene-perfluoroarene interactions are also present between the tetramers,i na ddition to C À H···p,C À H···F,a nd F···F interactions ( Figure S6). Each tetramer of 3m is centrosymmetric and, hence,c ontains molecules of opposite chirality (RRSS), leading to aracemic mixture (Figure 5b). Tetramers are arranged in sheets parallel to theb;c-plane ( Figure S6). In contrast, compound 3fcrystallizes in the non-centrosymmetric space group P1. There are 16 symmetry-independent molecules in the asymmetric unit (Z' = 16) of 3f,which build up four symmetry-independent hydrogen-bonded cyclic tetramers ( Figure S1). Each tetramer is constituted by molecules of the same chirality (RRRR or SSSS) ( Figure 5a). Thus,t he chirality of the four tetramers in the asymmetric unit, i.e., (RRRR)(SSSS)(RRRR)(SSSS), leads to aracemic mixture,as shown in Figures 5a,S1and S3. Te tramers of mixed chirality are arranged in sheets parallel to theb;c-plane with bromine atoms all pointing up or down within the sheet (Figures S2  and S3). Parallel sheets face each other either with the bromine atoms or without. In fact, crystals of 3frepresent one of the rare class of crystals for which Z' > 1. [33,34] While searching for as tructure of higher symmetry,t he cell parameters of 3f were also determined at 200 K. As this resulted in asimilar triclinic unit-cell metric as was observed  Figure 5. Compounds a) 3f and b) 3m self-assemble to form tetramers via OÀH···O hydrogen bonding and the corresponding graph set notation is R 4 4 (8). [31] p···p Stacking interactions between the bromophenyl or naphthyl and pentafluorophenyl groups, respectively, within the tetrameric unit are indicated by close C···C contacts (dashed lines). a) Each of the four symmetry-independent tetramers of 3fconsists of molecules of the same chirality (RRRR or SSSS). Only one tetramer (SSSS)i sshown here. b) In 3m,the tetramer is centrosymmetric with (RRSS)chirality of the molecules. at 100 K, the occurrence of aphase transition at temperatures between 100 Ka nd 200 Ki sunlikely.
Contrary to 3f and 3m,t he dominance of hydrogen bonding and absence of arene-perfluoroarene interactions in compounds 3l (space group P " 1), 3n and 4d(both space group C2/c)resulted in the formation of one-dimensional hydrogenbonded chains ( Figure 6). In 3land 3n,the intermolecular OÀ H···O and OÀH···N hydrogen bonding interaction takes place between the alcohol (O À H, donor) and the carboxaldehyde (O,a cceptor) and pyridyl (N,a cceptor) groups,r espectively, the latter having as tronger hydrogen bond acceptor ability compared to the alcohol group (Table S2). Depending on the position of the acceptor atom in the molecule,h ydrogenbonded chains are straight (3l, Figure 6a)orzig-zag-like (3n, Figure 6b). In 3l,e ach one-dimensional chain contains molecules of one particular chirality (either R or S), and chains of opposite chirality exhibit extensive p-stacking interaction between the phenyl groups.I nt his way,d oublestranded linear chains projecting the C 6 F 5 groups on both sides are formed, as shown in Figure 6a.The C 6 F 5 groups from neighboring strands undergo interdigitation and exhibit partial offset p···p interactions between fluorinated moieties and C À F···p interactions between phenyl and pentafluorophenyl groups ( Figures S4 and S5, Table S3). In 3n,o nedimensional zig-zag chains are formed by molecules of alternating chirality (RSRS…) (Figure 6b). Thepyridyl rings lie coplanar and the pentafluorophenyl groups interdigitate via partial offset p···p interactions to form ap arallel ribbonlike arrangement ( Figure S7, Table S3). This structure exhibits abilayer architecture as there are alternating hydrophobic and hydrophilic regions (Figures S7 and S8). [35] In 4d, corrugated one-dimensional chains are observed by the intermolecular OÀH···OÀH···hydrogen bonding interactions between the alcohol groups (Table S2), and molecules constituted of alternating pairs of same chirality (RRSSRRSS… as shown in Figure 6c and Figure S9). Other intermolecular interactions observed in 4d include CÀH···F,C ÀH···p,a nd very weak, strongly offset p···p interactions (Table S3).

Conclusion
We have demonstrated here the simple conditions for the 1,2-addition of aldehydes and ketones with polyfluorophenylboronate compounds.T his strategy has the following advantages:1 )transition metal-free catalyst system;2 )a variety of aromatic and aliphatic aldehydes were found to be suitable substrates for this reaction using pentafluorophenyl-Bpin in moderate to excellent yields;and 3) sterically hindered ketones also worked well to furnish the corresponding products.T his method also introduces the use of polyfluorophenyl-Bpin compounds instead of Grignard reagents for polyfluorophenylation of arylaldehyde and ketone substrates.Further studies of the synthesis and applications of polyfluorophenyl boronates are underway in our laboratory and will be reported in due course.