Pinacol Arylboronates from Aromatic Amines

Boronic acids and esters are extremely versatile intermediates which have the potential to be transformed into a variety of other functional groups. We have highlighted a couple of examples of these in Trifluoromethylation of arylboronic acids by Cu-mediated CF3 radicals and Borylation feast.

Wang has just published an interesting method for the synthesis of pinacol arylboronates from aromatic amines. Unlike most other methods for introducing a pinacol boronate ester motif this chemistry is metal free and instead uses tert-butyl nitrite under Sandmeyer-type reaction conditions (Scheme 1).

Scheme 1 – Different routes to arylboronic acids or arylboronates

This paper presets optimised reactions conditions which build on Wang’s initial communication and removes the need for benzoyl peroxide (BPO). The best temperature examined for the reaction was at 80°C. It was found that at this temperature the addition of the radical initiator BPO had a negligible effect (Table 1). It was also shown that the use of toluene, DCE or dioxane and the 2 alternative alkyl nitrites all negatively affected the yield.

Table 1 – Optimised reaction conditions for 2-amino benzonitrile.

These optimised conditions were directly compared to those in Wang’s initial communication and it was seen that there was an increase in yield of between a 5% and 44% in all of the reactions attempted (Scheme 2).

Scheme 3 – Scope of para-substituted aniline derivatives

When the reaction of meta, ortho or multi-substituted anilines was attempted lower yields were observed when compared to the para-substituted analogues (scheme 4). The steric hindrance of the ortho-substituted anilines could explain the lower yields observed for these reactions. Also, in general, it was seen that electron rich aromatic rings gave lower yields than those with electron withdrawing groups. This could be explained by the mechanism that Wang goes on to propose and the extra stability that an electron withdrawing group would give in the transition state.

Scheme 4 – Reaction of meta, ortho or multi-substituted anilines

Whilst expanding the scope of this reaction to include other aromatic and heterocyclic amines the previous observations were confirmed with electron deficient compounds giving higher yields than electron rich (scheme 5). The authors report that the electron rich aromatic amines are prone to oxidation by t-BuONO resulting in lower yields of the boronated product. They also note a lack of stability of these heterocyclic boronate esters to silica gel column chromatography.

Scheme 5 – Other aromatic anilines

To overcome the problem of purification and isolation of these unstable boronate esters Wang developed a sequential borylation and palladium catalysed cross coupling reaction (scheme 6). This procedure was able to give an increased combined yield of 41% for flavone 6e over 2 steps compared to only 32% for the boronate ester intermediate 5db (scheme 5). The low yields of compounds 6r and 6s could be due to the inherent instability of the α-hetero boronate ester intermediates to proto-deboronate.

Scheme 6 – Sequential borylation and palladium catalysed cross-coupling reaction

Wang has proposed a possible radical mechanism for this reaction (scheme 7). The first step is the formation of a tetra-coordinate boron complex (A) of B₂pin₂ with tert-butoxide anion. A single electron transfer then occurs between the ate complex A and the aryldiazonium moiety to give radicals B and C. Intermediate B is then able to extrude N₂ to give aryl radical D which is able to react with intermediate C to give the boronate ester product. To substantiate this mechanism Wang added 1.5 equivalents of a radical scavenger (TEMPO). He found that the reaction was sluggish and after 4 hours phenyl boronate ester was only formed in an 8% yield. In a control reaction he showed that no reaction was seen between TEMPO and B₂pin₂. In another reaction Wang heated a 1:1 mixture of BPO and B₂pin₂ at 100°C for 4 hours. This gave a 37% yield of phenyl boronate ester was formed which supports the aryl radical mechanism. However when he attempted to synthesise the aryl radical from PhI, Bu₃SnH and AIBN and then to react this with B₂pin₂ only a 7% yield of the desired product was isolated. Due to this result Wang was not able to rule out the possibility of an anionic mechanism of nucleophilic aromatic substitution of the aryldiazonium salt by the boron ate complex.

Scheme 7 – Possible reaction mechanism

This paper builds substantially on the work that Wang had previously published with a simplification of the reaction conditions and further exploration of the scope of this reaction. He has been able to overcome the problem of purifying unstable boronate esters and showed that they can be taken through a Suzuki reaction successfully without the need for any work-up or purification. Overall this reaction provides a very simple, practical and scalable method to synthesise boronate esters from various aromatic amines.