4-Formylphenylboronic acid

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4-Formylphenylboronic acid
Names
Preferred IUPAC name
4-(Dihydroxyboranyl)benzaldehyde
Identifiers
3D model (JSmol)
ECHA InfoCard 100.103.550 Edit this at Wikidata
UNII
  • B(C1=CC=C(C=C1)C=O)(O)O
Properties
C7H7BO3
Molar mass 149.94 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

4-Formylphenylboronic acid (4-FPBA) is a versatile synthetic building block and an important intermediate in the preparation of agrochemical and pharmaceutical active ingredients. The substance finds industrial application as a stabilizer and inhibitor for enzymes[1] and as a bactericide.

Synthesis

The synthesis of 4-formylyphenylboronic acid was reported by the group of Heinrich Nöth in 1990. 4-Bromobenzaldehyde was used as starting material.[2] The acetalization of the aldehyde group was carried out by standard methods[3] 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.

Synthese von 4-Formylphenylboronsäure nach Nöth
Synthese von 4-Formylphenylboronsäure nach Nöth

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)aluminumhydride, also on the kilogram scale.[4]

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.[5]

4-Formylphenylboronsäure mit n-Butyllithium
4-Formylphenylboronsäure mit n-Butyllithium

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.[6]

Synthese von 4-Formylphenylboronsäure aus 4-Chlorbenzaldehy und Lithiummetall
Synthese von 4-Formylphenylboronsäure aus 4-Chlorbenzaldehy und Lithiummetall

4-Formylphenylboronic acid can also be prepared by hydrolysis of potassium 4-formylphenyl-trifluoroborate by means of acidic alumina[7] or silicon dioxide.[8] As a rule, phenylboronic acids serve as starting compounds for the corresponding potassium aryl trifluoroborates.[9]

Properties

4-Formylphenyl boronic acid crystallizes in colorless needles[2] or is obtained as an odorless, whitish powder, which dissolves little in cold but better in hot water. The compound is quite stable[4] 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.[10]

Applications

4-Formylphenylboronic acid is used in Suzuki couplings, for example in the build up of pharmacologically active biphenyl compounds such as a precursor of the antihypertensive AT1 antagonist telmisartan in an improved synthesis:[11]

Synthese eines Telmisartan-Vorstufe durch Suzuki-Kupplung mit 4-FPBA
Synthese eines Telmisartan-Vorstufe durch Suzuki-Kupplung mit 4-FPBA

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):[12]

Aryl-Heteroarylkupplung
Aryl-Heteroarylkupplung

In a copper-mediated fluoroalkylation reaction, the boronic acid group of the 4-FPBA can be replaced with perfluorinated alkyl iodides (Rf-I) by a perfluoroalkyl chain under mild conditions.[13]

Umsetzung von 4-FPBA mit Perfluoralkyliodiden
Umsetzung von 4-FPBA mit Perfluoralkyliodiden

4-Formyphenylboronic acid is used industrially as an enzyme stabilizer for proteases and in particular for lipases in liquid detergent preparations.[1] 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.[14]

References

  1. ^ a b US 5972873, L.K. Nielsen, A. Deane-Wray, "4-Substituted-phenyl-boronic acids as enzyme stabilizers", published 1999-10-26, assigned to Novo Nordisk A/S 
  2. ^ a b H. Feulner; G. Linti; H. Nöth (1990), "Beiträge zur Chemie des Bors, 206. Darstellung und strukturelle Charakterisierung der p-Formylbenzolboronsäure", Chem. Ber. (in German), vol. 123, no. 9, pp. 1841–1843, doi:10.1002/cber.19901230915
  3. ^ Autorenkollektiv, Organikum, 24. Auflage, S. 481, Wiley-VCH, Weinheim, 2001, ISBN 978-3-527-33968-6
  4. ^ a b H. Jendralla; A. Wagner; M. Mollath; J. Wunner (1995), "Efficient, simple procedures for the large-scale preparation of buildings blocks for angiotensin (II) receptor antagonists", Liebigs Ann. Chem., vol. 1995, no. 7, pp. 1253–1257, doi:10.1002/jlac.1995199507166
  5. ^ Y. Kobayashi; Y. Tokoro; K. Watatani (1998), "Preparation of functionalized zinc borates and their coupling reactions with allylic acetates", Tetrahedron Lett., vol. 39, no. 41, pp. 7537–7540, doi:10.1016/S0040-4039(98)01639-6
  6. ^ US 6833470, A. Meudt, S. Scherer, F. Vollmüller, M. Erbes, "Method for producing formylphenylboronic acids", published 2004-12-21, assigned to Clariant GmbH 
  7. ^ G.W. Kabalka; V. Coltuclu (2009), "Thermal and microwave hydrolysis of organotrifluoroborates mediated by alumina", Tetrahedron Lett., vol. 50, no. 46, pp. 6271–6272, doi:10.1016/j.tetlet.2009.09.008
  8. ^ G.A. Molander; L.N. Cavalcanti; B. Canturk; P.-S. Pan; L.E. Kennedy (2009), "Efficient hydrolysis of organotrifluoroborates via silicagel and water", J. Org. Chem., vol. 74, no. 19, pp. 7364–7369, doi:10.1021/jo901441u, PMC 2763364, PMID 19743828
  9. ^ E. Vedejs; R.W. Chapman; S.C. Fields; S. Lin; M.R. Schimpf (1995), "Conversion of arylboronic acids into potassium aryltrifluoroborates: convenient precursors of arylboron difluoride Lewis acids", J. Org. Chem., vol. 60, no. 10, pp. 3020–3027, doi:10.1021/jo00115a016
  10. ^ G.K. Surya Prakash; F. Pertusati; G.A. Olah (2011), "HF-free, direct synthesis of tetrabutylammonium trifluoroborates", Synthesis, vol. 2011, no. 2, pp. 292–302, doi:10.1055/s-0030-1258370
  11. ^ A. S. Kumar; S. Ghosh; G.N. Mehta (2010), "Efficient and improved synthesis of Telmisartan", Beilstein J. Org. Chem., vol. 25, p. 6, doi:10.3762/bjoc.6.25, PMC 2874342, PMID 20502601
  12. ^ G. Singh; A. Singh; V. Singh; R.K. Verma; R. Mall (2016), "Novel benzimidazole derivatives as partial PPARγ agonists: synthesis, characterization, and docking studies", WJPPS, vol. 5, no. 7, pp. 1080–1091, doi:10.20959/wjpps20167-7143 (inactive 31 July 2022){{citation}}: CS1 maint: DOI inactive as of July 2022 (link)
  13. ^ Q. Qi; Q. Shen; L. Lu (2012), "Copper-mediated aerobic fluoroalkylation of arylboronic acids with fluoroalkyl iodides at room temperature", J. Am. Chem. Soc., vol. 134, no. 15, pp. 6548–6551, doi:10.1021/ja301705z, PMID 22458339
  14. ^ US 20130252315, T. O’Connell, S. Tondera, T. Weber, "Stabilized, liquid, enzyme-containing surfactant preparation", published 2013-9-26, assigned to Henkel AG & Co. KGaA 
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