Abstract: Synthesis of small-molecule conjugates capable of selective attachment to a peptide/protein backbone paves way for new therapeutic applications of protein modification. Sufficient inhibition or installation of function requires extensive design so the compound may identify and attach to the intended site. The utility of such an approach has prompted a number of applicable strategies and has rendered the development of new modification scaffolds less necessary. On the other hand, covalent modification to the biologics with ability to remove the conjugate via stimulus is underdeveloped, amplifying a current need to investigate the reversible potential for conjugation and deconjugation techniques in regard to molecular scaffolds. The investigation reported therein involves a small molecule design capable of conjugation and facile deconjugation from peptide/protein structure. Taking advantage of special reactivity between aldehyde and thiol, we utilize a number of readily available mercapto-benzaldehyde derivatives that have been synthesized by simple procedure and characterized by NMR. These compounds chemoselectively bind to backbone amino by institution of distinctive [3.3.1] and [2.2.1] bicyclic scaffolds. This protocol enables amino modification in a multi-component fashion in aqueous buffer and mild conditions, characterized by combination of HPLC and LC-MS methods. The various bicyclic modification derivatives were investigated for progression of the reversed reaction under mild condition, utilizing a commercially available amine reagent. In restoring the original protein motif, a full investigation of a heterocyclic derivative for reversible attachment to several linear peptides was subsequently performed. Upon completion, the effectiveness of this approach was demonstrated in the modification and quantifiable regeneration of insulin protein.

Purchased from AmBeed: 40138-16-7 ; 115290-70-5

Product Details of 2-FPBA

CAS No. :	40138-16-7
Formula :	C₇H₇BO₃
M.W :	149.94
SMILES Code :	O=CC1=CC=CC=C1B(O)O
MDL No. :	MFCD00151822
InChI Key :	DGUWACLYDSWXRZ-UHFFFAOYSA-N
Pubchem ID :	292189

Safety of 2-FPBA

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Application In Synthesis of 2-FPBA

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 40138-16-7 ]
Downstream synthetic route of [ 40138-16-7 ]

[ 40138-16-7 ] Synthesis Path-Upstream 1~1

1
[ 40138-16-7 ]
[ 124-40-3 ]
[ 85107-53-5 ]

References: [1] Journal of the American Chemical Society, 2015, vol. 137, # 20, p. 6492 - 6495.

[ 40138-16-7 ] Synthesis Path-Downstream 1~47

1
[ 40138-16-7 ]
[ 131818-17-2 ]
[ 870703-82-5 ]

References: [1]Tetrahedron Letters,1997,vol. 38,p. 5563 - 5566.

2
[ 3032-81-3 ]
[ 40138-16-7 ]
[ 656305-96-3 ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 355 - 374.

3
[ 21906-31-0 ]
[ 40138-16-7 ]
[ 2039-77-2 ]

References: [1]Journal of Organic Chemistry,2008,vol. 73,p. 495 - 501.
[2]Advanced Synthesis and Catalysis,2018,vol. 360,p. 1711 - 1718.

4
[ 40138-16-7 ]
[ 75279-55-9 ]
[ 1005346-91-7 ]

References: [1]Journal of Organic Chemistry,2008,vol. 73,p. 495 - 501.

5
[ 40138-16-7 ]
[ 18531-99-2 ]
[ 180683-64-1 ]
tert-butyl (E,1S,2S)-2-((2-((Sa)-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaborepin-4-yl)phenyl)methylideneamino)cyclohexylcarbamate [ No CAS ]

References: [1]Tetrahedron Asymmetry,2008,vol. 19,p. 489 - 494.

6
[ 3034-53-5 ]
[ 40138-16-7 ]
[ 223575-69-7 ]

Yield	Reaction Conditions	Operation in experiment
38%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 160℃; for 0.0833333h;Microwave irradiation;	6.21. Synthesis of (S)-2-Amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-thiazol-2-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid To a 40 ml microwave reactor, was added 1.04 g of 2-formyl phenylboronic acid (6.9 mmoles), 1.14 g of 2-bromo thiazole (6.9 mmoles), 240 mg of palladium bistriphenyl-phosphine dichloride (Pd(PPh3)2Cl2, 0.34 mmoles). Then, 13.8 ml of 1M Na2CO3 (13.8 mmoles) and 10 ml of CH3CN were added to the mixture. The reactor was sealed, and the reaction was run under microwave at 160 C. for 5 minutes. LCMS shows completion of the reaction with desired product. The reaction mixture was then poured into a separation funnel. Then 200 ml of methylene chloride and 100 ml of water were added for extraction. The methylene chloride layer was dried over MgSO4. Removal of solvent gave a crude product, which was purified by silica gel column chromatography eluding with hexanes/ethyl acetate mixture (5/1 to 2/1) to give pure 2-thiazol-2-yl-benzaldehyde (0.5 g, yield: 38%).
38%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In acetonitrile; at 160℃; for 0.0833333h;Sealed tube; Microwave irradiation;	To a 40 ml microwave reactor was added 1.04 g of 2-formylphenylboronic acid (6.9 mmol) of 1.14 g of 2-bromothiazole(6.9 mmol), 240 mg of bistriphenyl-phosphine palladium dichloride (Pd (PPh3) 2Cl2, 0.34 mmol). then,To the mixture was added 13.8 ml of 1 M Na2CO3 (13.8 mmol) and 10 ml of CH3CN. Sealed reactor,The reaction was run under microwave at 160 C for 5 minutes.LCMS shows the desired reaction of the desired product. The reaction mixture was then poured into a separation funnel. Add 200 ml of dichloromethaneAlkane and 100 ml of water for extraction. The dichloromethane layer was dried over MgSO4. The solvent was removed to give the crude product, which was passed through siliconThe column chromatography was eluted with a hexane / ethyl acetate mixture (5/1 to 2/1)To give pure 2-thiazol-2-yl-benzaldehyde (0.5 g, yield: 38%).
	With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; for 6h;Reflux;	Example 4 1-phenyl-8-[[2-(2-thiazolyl)phenyl]methyl]-1,3,8-triazaspiro[4.5]decan-4-one (Compound 24) Step A: To a mixture of 2-bromothiazole (826 mg, 4.99 mmol) and tetrakis(triphenylphosphine) palladium (0) (175 mg, 0.151 mmol) in 1,2-dimethoxyethane (20 mL) was added 2-formylbenzeneboronic acid (0.9017 g, 6.01 mmol) and 1 N aqueous NaHCO3 (8 mL). The resultant mixture was heated at reflux for 6 hrs. The reaction mixture was diluted with water and extracted with EtOAc (2 X 50 mL). The organic solution was dried over Na2SO4, filtered and concentrated. The crude product was purified by gradient flash chromatography (10% to 25% EtOAc in hexane) to yield 2-(2-thiazolyl)benzaldehyde as a white solid. MS (loop pos) MH+ = 190.1 1 H NMR (300 MHz, CDCl3) 7.50 (m, 1 H), 7.55-7.60 (m, 1 H), 7.65-7.70 (m, 1 H), 7.75-7.80 (m, 1 H), 7.95-7.97 (m, 1 H), 8.00-8.05 (m, 1 H), 10.5 (s, 1 H)

References: [1]Patent: US2008/153852,2008,A1 .Location in patent: Page/Page column 20.
[2]Patent: CN104045626,2017,B .Location in patent: Paragraph 0240.
[3]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 8607 - 8618.
[4]Patent: EP1392687,2017,B1 .Location in patent: Paragraph 0133-0136.

7
[ 3034-53-5 ]
palladium bistriphenyl-phosphine dichloride [ No CAS ]
[ 40138-16-7 ]
[ 223575-69-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In dichloromethane; water; acetonitrile;	6.54. Synthesis of (S)-2-Amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-thiazol-2-yl-phenyl)-ethoxyl-pyrimidin-4-yl}-phenyl)-propionic acid To a 40 ml microwave reactor, was added 1.04 g of 2-formyl phenylboronic acid (6.9 mmoles), 1.14 g of 2-bromo thiazole (6.9 mmoles), 240 mg of palladium bistriphenyl-phosphine dichloride (Pd(PPh3)2Cl2, 0.34 mmoles). Then, 13.8 ml of 1M Na2CO3 (13.8 mmoles) and 10 ml of CH3CN were added to the mixture. The reactor was sealed, and the reaction was run under microwave at 160 C. for 5 minutes. LCMS shows completion of the reaction with desired product. The reaction mixture was then poured into a separation funnel. Then 200 ml of methylene chloride and 100 ml of water were added for extraction. The methylene chloride layer was dried over MgSO4. Removal of solvent gave a crude product, which was purified by silica gel column chromatography eluding with hexanes/ethyl acetate mixture (5/1 to 2/1) to give pure 2-thiazol-2-yl-benzaldehyde (0.5 g, yield: 38%).

References: [1]Patent: US2009/29993,2009,A1 .

8
[ 40138-16-7 ]
[ 536-74-3 ]
[ 59046-72-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With nickel(II) (2-((3-methylthiophen-2-yl)methylene)hydrazinecarbothioamide)2.; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 100℃; for 5h;	General procedure: In an oven-dried round-bottom flask, a mixture of arylboronic acid (1.0 mmol), phenylacetylene (1.2 mmol), complex 1 (5.0 mol%), and 1,8-diazabicycloundec-7-ene(DBU) (2.0 mmol) in DMF (5 mL) was taken. The reaction mixture was stirred at 100C in air for 5 h. At the end of this time, the reaction mixture was diluted with EtOAc(20 mL) and washed with water (3 9 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the solvent was stripped off under reduced pressure. The residue was subjected to column chromatography on silica gel using ethyl acetate and n-hexane mixture to afford the desired product. The products were characterized by 1H and 13C NMR analysis.
78%	With anthracen-9-ylmethylene-(4-methoxyphenyl)amine; palladium diacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 100℃; for 2.5h;	General procedure: A mixture of arylboronic acid (1.0mmol), phenylacety-lene (1.2mmol), Pd(OAc) 2 (1.0mol%), L (1.0mol%) and 1,8-diazabicycloundec-7-ene (DBU) (2.0mmol) in DMF (5mL) was stirred at 100C in air for 4h. The reaction mixture was then diluted with EtOAc (20mL) and washed with water (3 × 10mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and the solvent was removed. The residue was subjected to column chromatography on silica gel using ethyl acetate and n-hexane mixture to afford the desired product. The products were characterized by 1 H and 13 C NMR analysis.

References: [1]Transition Metal Chemistry,2017,vol. 42,p. 579 - 585.
[2]Advanced Synthesis and Catalysis,2010,vol. 352,p. 458 - 462.
[3]Transition Metal Chemistry,2020,vol. 45,p. 325 - 331.
[4]Chemical Papers,2020,vol. 74,p. 3661 - 3669.

9
[ 54044-79-0 ]
[ 40138-16-7 ]
[ 1310531-83-9 ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 20 - 100℃;	To a solution of 2-bromo-5-methyl- l,3,4-thiadiazole (150 mg, 0.84 mmol) in 1,2- dimethoxyethane (5 mL) are added 2-formylphenylboronic acid (190 mg, 1.26 mmol), Pd(PPh3)4 (97 mg, 0.08 mmol) and Na2C03 (sat., 0.10 mL) at room temperature. The solution is heated to 100 C for 18 hours then cooled and poured into water and EtOAc. Layers are separated and the aqueous phase extracted with EtOAc (lx 10 mL). The combined organics are dried (MgS04), filtered and concentrated to give the crude product which is purified via flash chromatography (12g silica gel, 5-60% EtOAc/hexanes). The product-containing fractions are combined and concentrated to give 2-(5-methyl- 1,3,4- thiadiazol-2-yl)-benzaldehyde (100 mg, 58%) which is used without further purification.

References: [1]Patent: WO2011/68821,2011,A1 .Location in patent: Page/Page column 85.

10
[ 40138-16-7 ]
[ 932-87-6 ]
[ 59046-72-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	With copper(l) iodide; 8-quinolinol; sodium phosphate; In ethanol; at 80℃; for 24h;	General procedure: A 5.0 mL of reaction tube was charged with organoboron compound (1.0 mmol), alkynyl bromide (1.0 mmol), CuI (0.10 mmol), 8-hydroxyquinoline (0.20 mmol), ethanol (2.0 mmol). The mixture was stirred at 80 C for 24 h, and then washed with ethyl acetate (3.0 mL×3), the combined ethyl acetate was concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (petroleum ether as eluting agent) to give the corresponding pure cross-coupling product.

References: [1]Tetrahedron,2011,vol. 67,p. 4800 - 4806.

11
[ 40138-16-7 ]
[ 101335-11-9 ]
[ 1421751-51-0 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 1323 - 1340.

12
[ 40138-16-7 ]
[ 101335-11-9 ]
[ 1421751-75-8 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 1323 - 1340.

13
[ 62171-59-9 ]
[ 40138-16-7 ]
[ 1510683-06-3 ]

References: [1]Journal of the American Chemical Society,2013,vol. 135,p. 18815 - 18823.

14
[ 16870-28-3 ]
[ 40138-16-7 ]
[ 1261953-68-7 ]

References: [1]Journal of Physical Organic Chemistry,2011,vol. 24,p. 1151 - 1156.

15
[ 16870-28-3 ]
[ 40138-16-7 ]
[ 1261945-55-4 ]

References: [1]Journal of Physical Organic Chemistry,2011,vol. 24,p. 1151 - 1156.

16
[ 40138-16-7 ]
[ 99365-48-7 ]
[ 145865-34-5 ]

References: [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 164 - 170.

17
[ 16932-45-9 ]
[ 40138-16-7 ]
[ 1256479-82-9 ]

References: [1]European Journal of Organic Chemistry,2015,vol. 2015,p. 3558 - 3567.

18
[ 10421-85-9 ]
[ 40138-16-7 ]
[ 18741-85-0 ]
C₃₅H₂₄BClN₂O₃ [ No CAS ]
C₃₅H₂₄BClN₂O₃ [ No CAS ]

References: [1]RSC Advances,2015,vol. 5,p. 67277 - 67283.

19
[ 198544-94-4 ]
C₁₉H₁₆NO₅Pol [ No CAS ]
[ 35661-39-3 ]
[ 40138-16-7 ]
[ 92122-45-7 ]
[ 71989-14-5 ]
[ 104091-08-9 ]
H-Asp-Glu-Ala-Ala-Lys(PBA)-Ala-Ala-Lys-Asp-OH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		General procedure: Peptides were synthesized using standard, Fmoc-based, solid-phase protocols on a Liberty Microwave Peptide Synthesizer (CEM Corporation). The peptides Fmoc-Phe-Phe-Wang resin, Fmoc-Phe-Phe-RinkAmide AM resin, and Fmoc-Asp(OtBu)-Glu(OtBu)-(Ala)2-Lys(Mtt)-(Ala)2-Lys(Boc)-Asp(OtBu)-Wangresin were assembled from C-terminus to N-terminus on 0.1 mmol or 0.25 mmol scales using Fmoc-Phe-Wang resin, RinkAmide AM resin, and Fmoc-Asp(OtBu)- , respectively. Fmoc deprotection was accomplished using a 0.1 M solution of HOBt in 20:80 (vol:vol) piperidine:DMF. The resin was treated with two cycles of deprotect solution at 75 C for 180 s. Fmoc-protected amino acids were coupled to the deprotected amine ofthe resin-bound peptide using 5 eq. amino acid, 4.5 eq. HBTU, and 10 eq. DIEA relative to the resin loading. Each coupling reaction was conducted at 75 C for 180 s. The amino acids, HBTU, and DIEA were utilized as 0.2 M solutions in DMF, a 0.5 M solution in HBTU, and a 2 M solution in NMP, respectively.

References: [1]Tetrahedron Letters,2015,vol. 56,p. 5731 - 5734.

20
[ 766-36-9 ]
[ 40138-16-7 ]
2-ethyl-5-hydroxy-1-methylbenzo[c]pyrrolo[2,1-f ]-[1,2]azaborinin-3(5H)-one [ No CAS ]