Gold-Catalyzed Proto-and Deuterodeboronation

: A mild gold-catalyzed protodeboronation reaction, which does not require acid or base additives and can be carried out in “ green ” solvents, is described. As a result, the reaction is very functional-group-tolerant, even to acid-and base-sensitive functional groups, and should allow for the boronic acid group to be used as an e ﬀ ective traceless directing or blocking group. The reaction has also been extended to deuterodeboronations for regiospeci ﬁ c ipso -deuterations of aryls and heteroaryls from the corresponding organoboronic acid. Based on density functional theory calculations, a mechanism is proposed that involves nucleophilic attack of water at boron followed by rate-limiting B − C bond cleavage and facile protonolysis of a Au − σ - phenyl intermediate.


■ INTRODUCTION
Arylboronic acids are readily available and widely used substrates in organic chemistry. 1Traditionally, protodeboronation of arylboronic acids is usually considered an unwanted side product, 2 especially in Pd-catalyzed couplings (along with homocoupling and oxidation). 3Recently, however, the application of protodeboronation to organic synthesis has been elegantly demonstrated by several groups. 4In particular, Cheon and co-workers have demonstrated the utility of protodeboronations as a means of easily removing boronic acid groups after it has been used as a blocking or directing group (Scheme 1). 5 Overall, this renders the boronic acid moiety a traceless blocking/directing group, whereby the latter allows access to the difficult overall "meta-direction" with electrondonating X groups.
Unfortunately, there are current limitations as protodeboronation of arylboronic acids usually require harsh conditions such as strong bases or acids and are strongly substituent-dependent. 6hile Cheon's metal-free protodeboronation is a welcome exception, 5 the additive-free procedure is limited to electron-rich arylboronic acids only.Furthermore, unless the aryl has an orthoand para-OH group or very electron-donating NR 2 groups, the addition of acid (AcOH) or base (K 2 CO 3 ) is required for other electron-rich arylboronic acids, which precludes the use of acidand base-sensitive functional groups.In terms of transitionmetal-catalyzed protodeboronations, previously reported Cu-, 7 Ag-, 8 or Pd-catalyzed 9 methods typically require the addition of a stoichiometric base and can suffer from selectivity issues, such as coupling or dehalogenation products observed with the Pdcatalyzed method. 9Therefore, a mild and more general procedure, which is tolerant of both electron-donating and electron-withdrawing as well as various sensitive functional groups, is required in order to fully harness the potential of boronic acids as traceless blocking and directing groups.
In this article, we present a mild gold-catalyzed protodeboronation method, which not only is tolerant of various acid-and base-sensitive groups but also can be carried out in "green", environmentally benign, industrial-friendly solvents such as dimethylcarbonate. 10Furthermore, the procedure can be adapted to effect deuterodeboronations, which constitutes a practical and regiospecific ipso-deuteration technique.Synthetic procedures capable of incorporating deuterium (D) into organic molecules are highly sought after for wide ranging applications, 11 including mechanistic investigations, 12 analytical standards in stable-isotope tracer studies, 13 neutron scattering, 14 and drug targets with enhanced metabolic stability. 15Synthetic methods toward deuterated compounds are also regularly applied toward the tritium analogues, which are often used as radiotracers in the pharmaceutical industry. 11

■ RESULTS AND DISCUSSION
We originally discovered the gold-catalyzed protodeboronation reaction through a rather roundabout route.Our group has investigated many gold-catalyzed reactions using cyclopropenes 16 and allylic alcohols 17 as substrates.As part of these investigations, we explored the use of arylboronic acids as nucleophiles 18 in the gold(I)-catalyzed reaction with allylic 19 alcohols (Scheme 2) and cyclopropenes (Scheme 3).We were initially excited to find that arylations occurred under catalytic conditions to produce 3 and 5, respectively (Schemes 2 and 3). 20,21th the cyclopropene reaction, it soon became apparent (upon repeating the reaction at a lower temperature and monitoring over time) that the actual electrophile was not the cyclopropene 4 itself but was the allylic alcohol 6 that is formed upon addition of adventitious water to the gold intermediate 16a,c (Scheme 3, eq 2).The reaction with allylic alcohol (Scheme 2) was only ever successful with p-MeO-C 6 H 4 boronic acid 2a, and further control experiments suggest that the reaction in Scheme 2 simply works by gold(I)-catalyzed protodeboronation of the arylboronic acid 2a, followed by gold(I)-catalyzed Friedel− Crafts-type allylation 22 of the resulting aryl to form the observed product 3. 23 Despite this disappointment, we discovered that gold(I) can readily catalyze the protodeboronation of arylboronic acids without the need for acid or base additives. 24Since this coincided with a growing interest in protodeboronations as a tool in synthesis (vide ante), we set out to explore this reaction further.
Initially, a solvent screen was carried out on arylboronic acid 2b using PPh 3 AuNTf 2 as the catalyst 25 (Table 1).Unlike previously reported Cu-, 7 Ag-, 8 or Pd-catalyzed 9 methods which typically require the addition of a stoichiometric base, the gold(I)-catalyzed reaction proceeds well in the absence of any additives.Furthermore, the reaction does not require dry solvents 26 or an inert atmosphere and can be carried out easily in air.The solvent screen shows THF, 2-methyl THF, and dimethylcarbonate to all be suitable solvents for fully protodeboronating 2b to 7b at 50 °C for 24 h (entries 7−9).Since dimethylcarbonate has the most "green credentials" as a solvent, 10 we opted to adopt it as our solvent of choice for further optimization.
Next, we ascertained that lowering the catalyst loading or temperature from 5 mol % and 50 °C, respectively, produced incomplete conversions (Table 2), so the initial optimal conditions remained as shown in entry 5, Table 2.Under these conditions, however, it was soon evident that only electron-rich arylboronic acids could be fully protodeboronated (entries 1 and 2, Table 3); electron-poor arylboronic acids resulted in incomplete protodeboronation and would require slightly harsher conditions for good conversions (entries 3 and 4, Table 3).a Nonanhydrous solvents used.b Determined using 1 H NMR analysis of the crude reaction mixture using dimethylsulfone as an internal standard.a Determined using 1 H NMR analysis of the crude reaction mixture using dimethylsulfone as an internal standard.a Determined using 1 H NMR analysis of the crude reaction mixture using dimethylsulfone as an internal standard.b Increasing catalyst loading to 10 mol % or time to 48 h increases the yield to 57%.

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Pleasingly, slightly higher temperatures of 70−90 °C and utilizing microwave heating 27 allow for full conversion of both electron-donating and electron-withdrawing arylboronic acids in a much shorter reaction time (1−1.5 h, Table 4).For a more general procedure, 90 °C at 1 h was thus adopted.The ortho-, meta-, and para-substituted electron-rich arylboronic acids protodeboronated smoothly in excellent yields (entries 1−6; note that the lower yields of 7c and 7f reflect the slight volatility of the products).The ortho-, meta-, and para-substituted electron-poor arylboronic acids also protodeboronate smoothly under these conditions (entries 7 and 9−13).A carboxylic acid moiety, however, was found to inhibit protodeboronation (entry 8), but carboxylic acid products can nevertheless be readily obtained from protodeboronation and concurrent saponification of tert-butyl esters (entry 9).Unprotected base-sensitive ketone (entry 10) and ester functional groups (entries 7, 10, and 13) are tolerated, as are chloro-and bromoarylboronic acids (entries 15 and 16) but not aryl iodides (entry 17).Sterically bulky orthosubstituted substrates were also protodeboronated in high yields (entries 18−20), although longer reaction times of 2−3 h were necessary for full conversion of the bulkier substrates 2t and 2u (entries 19 and 20).Fluorene-2-boronic acid 2v, with a readily oxidizable benzylic position, is also a competent substrate (entry 21).
To our delight, even acid-sensitive THP acetal is tolerated (2x), as long as molecular sieves are added to the reaction (entry 22). 28,29Similarly, heteroarylboronic acids protodeboronate well (entries 23−26), including one with an acid-sensitive Boc group (2aa).There were, however, several arylboronic acids that failed to react under these conditions (entries 27−29).It is unclear why these arylboronic acids do not react, though inhibition of gold catalyst by the functional groups is a possibility.Nevertheless, the results presented in Table 4 demonstrate a wide substrate scope (electron-rich, electron-poor, sterically hindered, base-and acidsensitive) for the protodeboronation reaction.
As part of our investigations, a small screen of commercially available gold catalysts was also carried out (Table 5).While cationic gold(I) phosphines promote good conversion (Gagosz' catalyst 25 and Echavarren's catalysts, 30 entries 1 and 2), both gold(I) and gold(III) chlorides gave no conversion to Table 4. Arylboronic Acid Scope under Microwave Conditions a Commercial arylboronic acid; 10 equiv of H 2 O added to ensure any arylboroxine is hydrated to the arylboronic acid, except entries 1,2, 7, and 11. b 70 °C, 1.5 h.c Volatile product.d Carboxylic acid product.e 2 × 5 mol % of catalyst over 4 h.f Reaction was done in THF-d 8 , and yield was determined by 1 H NMR analysis using DMS as an internal standard.g 2 h.h 3 h.i 4 h.j Unactivated 4 Å MS were added.

The Journal of Organic Chemistry
Featured Article protodeboronated products (entries 3−6).For comparison with gold, a range of common palladium sources were also screened; no conversion was observed with Pd 2 (dba) 3 or Pd(PPh 3 ) 4 (entries 8 and 9), with only modest conversion with Pd(OAc) 2 (entry 7).
Next, arylboroxine 8b, 31 arylboronic ester 9b, 31 potassium aryltrifluoroborate 10b, 32 and MIDA-boronate 11b 33 were evaluated in the gold-catalyzed protodeboronation reaction in order to ascertain their reactivity relative to arylboronic acids 2 (Table 6).8b−11b do not react under these conditions (entries 2 and 4−6).However, since arylboroxine 8 is the dehydrated form of arylboronic acid 2, 31 addition of 10 equiv of H 2 O to the reacting mixture allows quantitative protodeboronation, presumably via preliminary in situ hydrolysis to the boronic acid 2b (entry 3).Since commercially available arylboronic acids are typically a mixture of boronic acid and the corresponding boroxine, 1 addition of 10 equiv of H 2 O was therefore adopted as the standard procedure in Table 4, to ensure reproducible results.In addition, the results in Table 6 show that orthogonal reactivity exists between arylboronic acids and the "protected" counterparts, arylboronic esters 9, aryltrifluoroborates 10, and MIDAboronates 11, which can potentially be exploited in synthesis.
To probe the mechanism of these protodeboronation reactions, we carried out DFT calculations (BP86-D3 level, correcting for THF solvent) 34 to model the reaction of PhB(OH) 2 with water at the {Au(PPh 3 )} + fragment.The computed profile (Figure 1) starts from the (Ph 3 P)Au(PhB-  Pd(PPh 3 ) 4 no conv.
a Determined using 1 H NMR analysis of the crude reaction mixture using dimethylsulfone as an internal standard.
Table 6.Effect of Other Boronic Acid Derivatives  An analogous study on the parent MIDA-boronate (11b, Table 6, Ar = Ph) provided a computed barrier of 39.5 kcal/mol, consistent with the fact that this species does not undergo protodeboronation.This reflects the presence of a saturated boron center in this species, which must undergo B−N bond cleavage (ΔG = +17.9kcal/mol) before nucleophilic attack can occur (see Supporting Information).
In order to provide evidence (or otherwise) for the ipsoselective protodeauration, the reaction was carried out in dried dimethylcarbonate with 10 equiv of added D 2 O under strictly anhydrous conditions (eq 1, Scheme 4).Indeed, deuteration occurs only at the ipso-position (d-7d, 83%), proving a regiospecific protodeauration step.This ipso-deuteration result also shows that the gold(I)catalyzed method can potentially be used as a regiospecific deuteration technique.The example shown in Scheme 4 is completely selective for the C bearing the boronic acid, and no deuteration is observed at any other position; therefore, it has potential as a selective deuterium-labeling technique for biochemical or mechanistic investigations.The reaction shown in Scheme 4 eq 1 was carried out under strictly anhydrous conditions (apart from the added D 2 O) in order to maximize the amount of D incorporation.In order to improve the practicality of the method, we decided to increase the amount of D 2 O in the reaction by using 1:1 THF/D 2 O as solvent (solubility is poor in D 2 O alone; see Table 1) (eq 2, Scheme 4).This practical deuteration method can be carried out readily in air and should be a mild, acid-and base-free deuteration method.Thus, a small substrate scope study was carried out (Table 7).
To our delight, electron-rich substrates deuterated regiospecifically in good yields (entries 1−3).The slightly lower 83% deuteration of d-7d compared to the full deuteration of d-7g and

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Featured Article d-7f is likely the result of the exchangeable phenolic proton present in the molecule.Unfortunately, arylboronic acids with electron-withdrawing groups reacted very sluggishly under these conditions and appear not to be good substrates for this method (entries 4 and 5).Nevertheless, this deuterodeboronation method is therefore complementary to the deuterodecarboxylation methods described previously, which were mainly suitable for electron-withdrawing aryls. 37The sterically hindered position in 2s is tolerated well (entry 6).Pleasingly, selective deuteration of heterocycles also proceeds well (entries 7−9).Therefore, from the substrate scope study shown in Table 7, it appears that the percent deuteration is generally excellent (>95%), except in cases where an exchanging proton is present in the substrate (entry 1, 83% D).In terms of conversions, the procedure works best with electron-rich aryl-or heteroarylboronic acid substrates.

■ CONCLUSION
In conclusion, we have developed a mild gold(I)-catalyzed protodeboronation method that can be used in "green" solvents, is tolerant of a variety of functional groups (including acid-and base-sensitive groups), and is general to a wide range of arylboronic acids.It is hoped that this simple, mild, and general protodeboronation method will enable the more widespread use of boronic acids as blocking/directing groups.DFT calculations propose a mechanism that involves sequential nucleophilic attack of water at boron, rate-limiting B−C bond cleavage, and facile protonolysis of a Au−σ-phenyl intermediate.
In the presence of D 2 O, it can also be utilized as a mild, baseand acid-free regiospecific ipso-deuteration technique.The deuterodeboronation works smoothly for heteroaryl and electron-rich arylboronic acid substrates, which makes it complementary to deuterodecarboxylation methods which are limited to electron-withdrawing aryls.We envisage that this method should see applications in selective deuterium labeling of compounds for biochemical or mechanistic investigations.
Computational Details.Calculations were run with Gaussian 03, revision D.01, 61 with PCM solvent corrections run with Gaussian 09, revision A.02. 62 Geometry optimizations were performed using the BP86 functional 63 with Au and P centers described with the Stuttgart RECPs and associated basis sets 64 (with added d-orbital polarization on P (ζ = 0.387)) 65 and 6-31G** basis sets for all other atoms. 66All stationary points were fully characterized via analytical frequency calculations as either minima (all positive eigenvalues) or transition states (one negative eigenvalue).Frequency calculations also provided a free energy in the gas phase, computed at 298.15 K and 1 atm.For transition states, IRC calculations and subsequent geometry optimizations were used to confirm the minima linked by each transition state.Energies reported in the text are based on the gas-phase free energies and incorporate a correction for dispersion effects using Grimme's D3 parameter set 67 (i.e., BP86-D3) as well as solvation (PCM approach) in THF.
■ ASSOCIATED CONTENT * S Supporting Information NMR spectra and computational data.The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.5b01041.

Notes
The authors declare no competing financial interest.

Scheme 2 .
Scheme 2. Preliminary Results on Gold-Catalyzed Arylations with Allylic Alcohols in which the boronic acid binds to Au in an η 1 -fashion via the ipso-carbon (Au−C 1 = 2.26 Å, C 1 − B = 1.61 Å; see Figure2for atom labeling).35No stable η 2adducts were located.Two additional waters were included in the calculations because pathways based on a single water were found to have prohibitively high barriers, while tests with three water molecules exhibited a mechanism and energetics similar to those seen with two waters (see Supporting Information).Excess water is always present in the most efficient synthetic protocols.In I•2H 2 O (G = 0.0 kcal/mol), the two water molecules form a square H-bonded array with the OH groups of the boronic acid.The reaction then starts from a higher energy conformer of this species, Ia•2H 2 O (G = +4.1 kcal/mol), in which the added waters are located between the Au and B centers.From this position, one water can attack boron to form a weakly bound adduct, II• 2H 2 O (G = +8.4kcal/mol, B−O 1 = 1.79 Å, B−C 1 = 1.64 Å).B− C 1 bond cleavage then proceeds via TS(II−III)•2H 2 O at +18.4 kcal/mol with further shortening of the B−O 1 distance to 1.54 Å and elongation of B−C 1 to 2.08 Å (see Figure 2).This leads to III•2H 2 O, which features a σ-Ph ligand (Au−C 1 = 2.06 Å) and a protonated boric acid−water cluster situated above the phenyl ring with one short Au•••H contact (2.28 Å).The presence of a second water molecule facilitates this step by stabilizing the proton released upon nucleophilic attack.Protodeboronation is then completed by rotation of the B(OH) 2 (H 2 O) + •H 2 O moiety to a perpendicular position and delivery of a proton onto the ipso-C via TS(III−IV)•2H 2 O (G = +1.9kcal/mol; O 1 −H 1 = 1.15 Å, C 1 •••H 1 = 1.54 Å, Au−C 1 = 2.11 Å).This proton transfer is facilitated by H-bonding to the external water molecule and leads to IV•B(OH) 3 •H 2 O (G = −15.5 kcal/mol) in which a linear (Ph 3 P)Au(η 2 -C 6 H 6 ) complex interacts weakly with the B(OH) 3 • H 2 O cluster.Protodeboronation therefore proceeds with an overall barrier of 18.4 kcal/mol, with the rate-limiting transition

a
Determined using1 H NMR analysis of the crude reaction mixture using dimethylsulfone as an internal standard.b Arylboronic acid freshly recrystallized from water.c Arylboroxine formed from dehydrating arylboronic acid 2b via heating under vacuum.d 10 equiv of H 2 O added to the reaction mixture.

Table
. Solvent Screen

Table 2 .
Varying Catalyst Loading and Temperatures entry temp (°C) mol % of catalyst yield (%) a

Table 3
. Electron-Poor Arylboronic Acids Are Not Fully Converted Using Initial Conditions entry aryl yield (%) a 1 m,p-(OMe) 2 C