111771-08-5|2-Fluoro-6-iodobenzoic acid| Ambeed

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Quality Control of [ 111771-08-5 ] Purity: 98% SDS Specification

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Energy-Activated and Diversifiable Aryne Precursors from Carboxylic Acids

Seong, Chris ; Kargbo, Sallu ; Yu, Chia-Ling ; Gibney, Daniel ; Boyn, Jan-Niklas ; Roberts, Courtney

DOI: 10.26434/chemrxiv-2024-t6pcq ChemRxiv,2024.

Abstract: Densely substituted arene rings are ubiquitous in pharmaceuticals and agrochemicals which support human health and wellbeing. Arynes–a triple bond in a benzene ring–are an intriguing solution to the problem of generating decorated arenes. State-of-the-art aryne precursors are plagued by two issues: 1) the additives required for activation are incompatible with many desirable functional groups intrinsic to the aryne itself as well as the coupling partners which limits the scope, and 2) derivatization of the precursors requires lengthy linear sequences often using harsh conditions rendering them impractical for discovery chemists. Here, we show the design of an aryne precursor made in a single step from a commercially available carboxylic acid and then derivatized in a single S_NAr step. Unprecedented aryne activation proceeds using blue light or mild heat, avoiding the use of additives. The model system for this precursor incorporates an ortho-amino group in the final stage because anilines are found in 40% of medicinal chemistry patents and are highly underrepresented in aryne methodology. These precursors have the potential to supersede existing precursors and enable broad access to this desirable synthon.

Purchased from AmBeed: 111771-08-5

Product Details of [ 111771-08-5 ]

CAS No. :	111771-08-5
Formula :	C₇H₄FIO₂
M.W :	266.01
SMILES Code :	O=C(O)C1=C(I)C=CC=C1F
MDL No. :	MFCD00042289
InChI Key :	CYCXAPWOBWWNRK-UHFFFAOYSA-N
Pubchem ID :	2733302

Safety of [ 111771-08-5 ]

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

Computational Chemistry of [ 111771-08-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	46.08
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	37.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.35
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.2
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.55
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.94
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.61
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.33

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.21
Solubility	0.163 mg/ml ; 0.000613 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.62
Solubility	0.642 mg/ml ; 0.00241 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.0
Solubility	0.265 mg/ml ; 0.000995 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.36 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.75

Application In Synthesis of [ 111771-08-5 ]

* 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.

Downstream synthetic route of [ 111771-08-5 ]

[ 111771-08-5 ] Synthesis Path-Downstream 1~35

1
[ 111771-08-5 ]
[ 111771-12-1 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0℃;	To a heterogeneous mixture of <strong>[111771-08-5]2-fluoro-6-iodobenzoic acid</strong> (1 .51 g, 5.66 mmol) at 0 C in DCM (28 mL) was added oxalyl chloride (0.635 mL, 7.36 mmol) followed by DMF (0.15 mL). Gas evolution commenced immediately and after 5 min the ice bath was removed. When gas evolution had ceased and the mixture was homogeneous an aliquot was removed and quenched with MeOH. Formation of the methyl ester was confirmed by HPLC and the mixture was concentrated in vacuo. The viscous liquid was dissolved in fresh DCM (28 mL) and treated with solid N-hydroxyacetamidine (503 mg, 6.79 mmol) in several portions followed by TEA (1 .2 mL, 8.49 mmol) at 0 C. After stirring for 14 h at ambient temperature the mixture was washed with saturated aqueous NaHCO3 solution. The combined organic extracts were dried over Na2SO4, filtered andconcentrated in vacuo. Chromatography (Hex to 100% EtOAc/Hex) afforded the desired product as a colorless oil (1 .57 g, 86%). MS (ESI) mass calculated for C9H8FIN2O2, 321 .96; m/z found, 323.0. 1 H NMR (500 MHz, CDCI3): 7.70 - 7.65 (m, 1 H), 7.15 - 7.1 1 (m, 2H), 4.87 (br s, 2H), 2.06 (s, 3H).
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃;	Step A: (Z)-N'-((2-Fluoro-6-iodobenzoyl)oxy)acetimidamide. To a heterogeneous mixture of <strong>[111771-08-5]2-fluoro-6-iodobenzoic acid</strong> (1 .51 g, 5.66 mmol) at 0 C in DCM (28 mL) was added oxalyl chloride (0.635 mL, 7.36 mmol) followed by DMF (0.15 mL). Gas evolution commenced immediately and after 5 min the ice bath was removed. When gas evolution had ceased and the mixture was homogeneous an aliquot was removed and quenched with MeOH. Formation of the methyl ester was confirmed by HPLC and the mixture was concentrated in vacuo. The viscous liquid was dissolved in fresh DCM (28 mL) and treated with solid N-hydroxyacetamidine (503 mg, 6.79 mmol) in several portions followed by TEA (1 .2 mL, 8.49 mmol) at 0 C. After stirring for 14 h at ambient temperature the mixture was washed with saturated aqueous NaHCO3 solution. The combined organic extracts were dried over Na2SO4, filtered andconcentrated in vacuo. Chromatography (Hex to 100% EtOAc/Hex) afforded the desired product as a colorless oil (1 .57 g, 86%). MS (ESI) mass calculated for C9H8FIN2O2, 321 .96; m/z found, 323.0. 1 H NMR (500 MHz, CDCI3): 7.70 - 7.65 (m, 1 H), 7.15 - 7.1 1 (m, 2H), 4.87 (br s, 2H), 2.06 (s, 3H).
	With oxalyl dichloride; In dichloromethane; at 20℃; for 1h;Inert atmosphere;	Oxalyl chloride (2.5 ml, 28.66 mmol, 1.5 eq.) was added at room temperature to a suspension of <strong>[111771-08-5]2-fluoro-6-iodobenzoic acid</strong> (5.1 g, 19.17 mmol, 1 eq.) in 40 ml of dry DCM under nitrogen atmosphere. A few drops of dry DMF were added and the mixture was stirred at room temperature for 1 h. The solvent was removed by distillation. The obtainedresidue was taken up in acetonitrile, which was distilled again, to remove excess acidity. The resulting brown oil was dissolved in dry DCM and the resulting solution was drop- wise added to a suspension of potassium carbonate (7g, 50.6mmol, 2.6 eq.) in 20 ml of dry methanol. The reaction mixture was then stirred at room temperature overnight.The next morning the solids were filtered away and washed with DCM. The volume of theliquid phase was reduced by vacuum distillation. The resulting slurry was taken up inDCM and filtered again.The clear liquid phase was then dried over sodium sulphate, filtered and evaporated dodryness to give 4.27 g (15.25 mmol) of (D77) as a yellow oil.MS (ESI) mlz: 219 [M+H].1H NMR (ODd3) 5 ppm = 7.78 -7.60 (m, 1 H), 7.28 (s, 1 H), 7.14 (dd, J = 3.7, 8.1 Hz, 2 H), 4.00 (s, 3 H).

With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;

Oxalyl chloride (2.5 ml, 28.66 mmol, 1.5 eq.) was added at room temperature to a suspension of [111771-08-5]2-fluoro-6-iodobenzoic acid (5.1 g, 19.17 mmol, 1 eq.) in 40 ml of dry DCM under nitrogen atmosphere. A few drops of dry DMF were added and the mixture was stirred at room temperature for 1 h. The solvent was removed by distillation. The obtained residue was taken up in acetonitrile, which was distilled again, to remove excess acidity. The resulting brown oil was dissolved in dry DCM and the resulting solution was dropwise added to a suspension of potassium carbonate (7 g, 50.6 mmol, 2.6 eq.) in 20 ml of dry methanol. The reaction mixture was then stirred at room temperature overnight. The next morning the solids were filtered away and washed with DCM. The volume of the liquid phase was reduced by vacuum distillation. The resulting slurry was taken up in DCM and filtered again. The clear liquid phase was then dried over sodium sulphate, filtered and evaporated do dryness to give 4.27 g (15.25 mmol) of (D77) as a yellow oil. MS (ESI) m/z: 219 [M+H]+. 1H NMR (CDCl3) delta ppm=7.78-7.60 (m, 1H), 7.28 (s, 1H), 7.14 (dd, J=3.7, 8.1 Hz, 2H), 4.00 (s, 3H).

References: [1]Journal of Organic Chemistry,1988,vol. 53,p. 345 - 352.
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 272 - 282.
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 3047 - 3062.
[4]Patent: WO2011/50200,2011,A1 .Location in patent: Page/Page column 87.
[5]Patent: WO2011/50202,2011,A1 .Location in patent: Page/Page column 59.
[6]Patent: WO2013/92893,2013,A1 .Location in patent: Page/Page column 44; 45.
[7]Patent: US2014/357653,2014,A1 .Location in patent: Paragraph 0280; 0281; 0282; 0283; 0284; 0285.
[8]Organic Letters,2019,vol. 21,p. 9960 - 9964.
[9]Journal of Medicinal Chemistry,2019,vol. 62,p. 10221 - 10244.

2
[ 504-02-9 ]
[ 111771-08-5 ]
2-fluoro-6-iodo-benzoic acid 3-oxo-cyclohex-1-enyl ester [ No CAS ]

References: [1]Tetrahedron Letters,1999,vol. 40,p. 7595 - 7598.
[2]Tetrahedron,2003,vol. 59,p. 4237 - 4247.

3
[ 124-38-9 ]
[ 1121-86-4 ]
[ 111771-08-5 ]

Yield	Reaction Conditions	Operation in experiment
33%		n-BuLi (120 rnL) was added dropwise to a solution of diisopropylamine (33.33 g, 330.00 mmol) in ether (300 rnL) at -700C. The resulting solution was stirred at -700C for 1 h followed by addition of a solution of l-fluoro-3-iodobenzene (22.2 g, 100.00 mmol) in ether (100 mL). After stirring for 1 h (at -700C), CO2 (gas) was bubbled in the reaction mixture. The resulting solution was stirred at -500C for 1 h. The resulting solution was extracted with water (1x300 mL). Adjustment of the pH to 1 was accomplished by the addition of HCl (4M) and the aqueous layer was extracted with EtOAc (3x300 mL). The organics were combined, washed with brine (2x100 mL), dried over Na2SO4, and evaporated to dryness to afford 8 g (33%) of 2-fluoro-6- iodobenzoic acid as a yellow solid.

References: [1]European Journal of Organic Chemistry,2002,p. 3351 - 3358.
[2]Synthesis,2005,p. 617 - 621.
[3]Patent: WO2008/103615,2008,A1 .Location in patent: Page/Page column 41.

4
[ 119072-55-8 ]
[ 111771-08-5 ]
[ 107-11-9 ]
[ 552-89-6 ]
N-allyl-N-[tert-butylcarbamoyl-(2-nitro-phenyl)-methyl]-2-fluoro-6-iodo-benzamide [ No CAS ]

References: [1]Organic Letters,2004,vol. 6,p. 3155 - 3158.

5
[ 186581-53-3 ]
[ 111771-08-5 ]
[ 146014-66-6 ]

References: [1]Synthesis,2005,p. 617 - 621.

6
[ 124-38-9 ]
[ 851368-08-6 ]
[ 2252-37-1 ]
[ 111771-08-5 ]

References: [1]Synthesis,2005,p. 617 - 621.

7
[ 53915-69-8 ]
[ 111771-08-5 ]
8-fluoro-3-methylisochromen-1-one [ No CAS ]

References: [1]Journal of Organic Chemistry,2005,vol. 70,p. 6669 - 6675.

8
tributyl-hepta-1,2-dienyl-stannane [ No CAS ]
[ 111771-08-5 ]
8-fluoro-3-pentyl-isochromen-1-one [ No CAS ]

References: [1]Journal of Organic Chemistry,2005,vol. 70,p. 6669 - 6675.

9
[ 111771-08-5 ]
[ 41391-54-2 ]
8-fluoro-3-ethyl-1H-isochromen-1-one [ No CAS ]

References: [1]Journal of Organic Chemistry,2005,vol. 70,p. 6669 - 6675.

10
[ 111771-08-5 ]
[ 18107-18-1 ]
[ 146014-66-6 ]