4-Formylphenylboronic acid

The synthesis of 4-formylyphenylboronic acid was reported by the group of Heinrich Nöth in 1990. 4-Bromobenzaldehyde was used as starting material.{{citation|author1=H. Feulner|author2=G. Linti|author3=H. Nöth|journal=Chem. Ber.|title=Beiträge zur Chemie des Bors, 206. Darstellung und strukturelle Charakterisierung der p-Formylbenzolboronsäure|volume=123|issue=9|pages=1841–1843|date= 1990|language=German|doi=10.1002/cber.19901230915}} The acetalization of the aldehyde group was carried out by standard methodsAutorenkollektiv, Organikum, 24. Auflage, S. 481, Wiley-VCH, Weinheim, 2001, {{ISBN|978-3-527-33968-6}} using diethoxymethoxyethane and ethanol to give 1-bromo-4-(diethoxymethyl)benzene. The formation of the Grignard compound with magnesium requires 1,2-dibromoethane and activation with ultrasound. Reaction with tri-n-butyl borate leads to the protected aryl boronic ester which gives after acidic work-up the target product in 78% yield.

File:4-Formylphenylboronsäure Synthese nach Nöth.svg

The same reactants are forming with the aryl boronic ester at −60 °C 4-formylyphenylboronic acid with a 99% yield when activated with sodium bis(2-methoxyethoxy)aluminiumhydride, also on the kilogram scale.{{citation|author1=H. Jendralla|author2=A. Wagner|author3=M. Mollath|author4=J. Wunner|journal=Liebigs Ann. Chem.|title=Efficient, simple procedures for the large-scale preparation of buildings blocks for angiotensin (II) receptor antagonists|volume=1995|issue=7|pages=1253–1257|date= 1995|doi=10.1002/jlac.1995199507166}}

When the aryllithium compound of 1-bromo-4-(diethoxymethyl)benzene is used with triisopropylborate at −78 °C instead of the Grignard compound (via n-butyllithium) 4-formylphenylboronic acid is obtained in 99% crude yield.{{citation|author1=Y. Kobayashi|author2=Y. Tokoro|author3=K. Watatani|journal=Tetrahedron Lett.|title=Preparation of functionalized zinc borates and their coupling reactions with allylic acetates|volume=39|issue=41|pages=7537–7540|date= 1998|doi=10.1016/S0040-4039(98)01639-6}}

File:4-Formylphenylboronsäure Synthese nach Kobayashi.svg

Disadvantages of both routes are the high price of the educts used (such as 4-bromobenzaldehyde, boronic esters of higher alcohols and butyllithium) as well as in the Nöth route the difficult workup after the hydrolysis by n-butanol. More recently, an improved process has been patented using less expensive starting materials such as 4-chlorobenzaldehyde, metallic lithium and trimethyl borate.{{cite patent|country = US|number =6833470 |title=Method for producing formylphenylboronic acids |pubdate =2004-12-21|fdate =2001-11-30 |inventor =A. Meudt, S. Scherer, F. Vollmüller, M. Erbes |assign1 =Clariant GmbH}}

File:4-Formylphenylboronsäure Clariant-Synthese.svg

4-Formylphenylboronic acid can also be prepared by hydrolysis of potassium 4-formylphenyl-trifluoroborate by means of acidic alumina{{citation|author1=G.W. Kabalka|author2=V. Coltuclu|journal=Tetrahedron Lett.|title=Thermal and microwave hydrolysis of organotrifluoroborates mediated by alumina|volume=50|issue=46|pages=6271–6272|date= 2009|doi=10.1016/j.tetlet.2009.09.008}} or silicon dioxide.{{citation|author1=G.A. Molander|author2=L.N. Cavalcanti|author3=B. Canturk|author4=P.-S. Pan|author5=L.E. Kennedy|journal=J. Org. Chem.|title=Efficient hydrolysis of organotrifluoroborates via silicagel and water|volume=74|issue=19|pages=7364–7369|date= 2009|doi=10.1021/jo901441u|pmid=19743828|pmc=2763364}} As a rule, phenylboronic acids serve as starting compounds for the corresponding potassium aryl trifluoroborates.{{citation|author1=E. Vedejs|author2=R.W. Chapman|author3=S.C. Fields|author4=S. Lin|author5=M.R. Schimpf|journal=J. Org. Chem.|title=Conversion of arylboronic acids into potassium aryltrifluoroborates: convenient precursors of arylboron difluoride Lewis acids|volume=60|issue=10|pages=3020–3027|date= 1995|doi=10.1021/jo00115a016}}

4-Formylphenyl boronic acid crystallizes in colorless needles or is obtained as an odorless, whitish powder, which dissolves little in cold but better in hot water. The compound is quite stable and readily forms dimers and cyclic trimeric anhydrides, which complicate purification and tend to protodeboronize, a secondary reaction that occurs frequently in the Suzuki coupling, with elimination of the boronic acid function.{{citation|author1=G.K. Surya Prakash|author2=F. Pertusati|author3=G.A. Olah|journal=Synthesis|title=HF-free, direct synthesis of tetrabutylammonium trifluoroborates|volume=2011|issue=2|pages=292–302|date= 2011|doi=10.1055/s-0030-1258370}}

4-Formylphenylboronic acid is used in Suzuki couplings, for example in the build up of biphenyl compounds such as a precursor of the antihypertensive AT1 antagonist telmisartan in an improved synthesis:{{citation|author1=A. S. Kumar|author2=S. Ghosh|author3=G.N. Mehta|journal=Beilstein J. Org. Chem.|title=Efficient and improved synthesis of Telmisartan|volume=25|pages=6|date= 2010|doi=10.3762/bjoc.6.25|pmid=20502601|pmc=2874342}}

File:Telmisartan-Vorstufe durch Suzuki-Kupplung mit 4-FPBA.svg

Also palladium-catalyzed aryl heteroaryl linkages after Suzuki use 4-formylphenylboronic acid as a molecular building block, as for instance in the synthesis of aryl-benzimidazole derivatives (which bind to peroxisome-proliferator-activated receptors (PPARγ) and activate the expression of a variety of genes):{{cn|date=July 2023}}

File:Aryl-Heteroarylkupplung nach Suzuki.svg

In a copper-mediated fluoroalkylation reaction, the boronic acid group of the 4-FPBA can be replaced with perfluorinated alkyl iodides (R_f-I) by a perfluoroalkyl chain under mild conditions.{{citation|author1=Q. Qi|author2=Q. Shen|author3=L. Lu|journal=J. Am. Chem. Soc.|title=Copper-mediated aerobic fluoroalkylation of arylboronic acids with fluoroalkyl iodides at room temperature|volume=134|issue=15|pages=6548–6551|date= 2012|doi=10.1021/ja301705z|pmid=22458339|bibcode=2012JAChS.134.6548Q |url=https://figshare.com/articles/journal_contribution/2530234}}

File:Fluoralkylierung von 4-FPBA.svg

4-Formyphenylboronic acid is used industrially as an enzyme stabilizer for proteases and in particular for lipases in liquid detergent preparations. The addition of 4-FPBA in amounts < 0.08 wt% in the formulation reduces the loss of hydrolytic activity of the enzymes used and increases the storage stability of enzyme-containing liquid detergents.{{cite patent|country = US|number =20130252315 |title=Stabilized, liquid, enzyme-containing surfactant preparation |pubdate =2013-9-26 |fdate =2013-5-14 |inventor =T. O’Connell, S. Tondera, T. Weber | assign1 =Henkel AG & Co. KGaA}}

The substance is an inhibitor for some enzymes{{cite patent|country = US|number =5972873 |title=4-Substituted-phenyl-boronic acids as enzyme stabilizers |pubdate =1999-10-26 |fdate =1997-11-21 |inventor =L.K. Nielsen, A. Deane-Wray | assign1 =Novo Nordisk A/S}} and as a bactericide.{{cn|date=January 2025}}

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Category:Benzaldehydes

Category:Boronic acids