16052-42-9

Basic information

• Product Name: (-)-MENTHYL CHLORIDE
• Synonyms: (-)-MENTHYL CHLORIDE;L-(-)-MENTHYL CHLORIDE;L-MENTHYL CHLORIDE;(-)-3-CHLORO-P-MENTHANE;(1R)-(-)-MENTHYL CHLORIDE;(1S,2R,4R)-2-CHLORO-1-ISOPROPYL-1-METHYLCYCLOHEXANE;[1S-(1ALPHA,2BETA,4BETA)]-2-CHLORO-4-METHYL-1-(METHYLETHYL)CYCLOHEXANE;2-Chloro-1-isopropyl-4-methylcyclohexane
• CAS NO: 16052-42-9
• Molecular Formula: C₁₀H₁₉Cl
• Molecular Weight: 174.71
• EINECS: 240-200-7
• Product Categories: Biochemistry;Monocyclic Monoterpenes;Terpenes
• Mol File: 16052-42-9.mol
• Article Data: 27

Chemical Properties

• Melting Point: −20-−16.5 °C(lit.)
• Boiling Point: 101-101.5 °C21 mm Hg(lit.)
• Flash Point: 174 °F
• Appearance: colorless liquid
• Density: 0.936 g/mL at 25 °C(lit.)
• Vapor Pressure: 0.209mmHg at 25°C
• Refractive Index: n20/D 1.464
• BRN: 1902297
• CAS DataBase Reference: (-)-MENTHYL CHLORIDE(CAS DataBase Reference)
• NIST Chemistry Reference: (-)-MENTHYL CHLORIDE(16052-42-9)
• EPA Substance Registry System: (-)-MENTHYL CHLORIDE(16052-42-9)

Safety Data

• Safety Statements: 23-24/25
• WGK Germany: 3
• HazardClass: IRRITANT
• Hazardous Substances Data: 16052-42-9(Hazardous Substances Data)

Usage

Uses

2-Chloro-4-methyl-1-(1-methylethyl)-Cyclohexane is a useful building block for organic synthesis.

Purification Methods

Dissolve menthyl chloride in pet ether (b 40-60o), wash with H2O, conc H2SO4 until no discoloration of the organic layer occurs (care with conc H2SO4 during shaking in a separating funnel), again with H2O and dry it (MgSO4). Evaporate and distil the residual oil through a Claisen head with a Vigreux neck ( p 11) of ca 40 cm length. [Smith & Wright J Org Chem 17 1116 1952, Barton et al. J Chem Soc 453 1952, Beilstein 5 III 134.]

InChI:InChI=1/C10H19Cl/c1-7(2)9-5-4-8(3)6-10(9)11/h7-10H,4-6H2,1-3H3/t8-,9+,10-/m1/s1

Synthetic route

(-)-menthol (2216-51-5) → (1R,2S,5R)-menthyl chloride (16052-42-9)

Conditions	Yield
With hydrogenchloride; zinc(II) chloride In water at 0 - 20℃; for 48h; Schlenk technique;	99%
With hydrogenchloride; zinc(II) chloride Substitution;	92%
With hydrogenchloride; zinc(II) chloride at 60℃; for 12h;	91%

(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl methanesulfonate (61548-81-0) → (1R,2S,5R)-menthyl chloride (16052-42-9)

Conditions	Yield
With chloro-trimethyl-silane; iron(III)-acetylacetonate In dichloromethane at 20℃; for 3h; Inert atmosphere;	99%

(1S,2R,5S)-(+)-menthol (15356-60-2) → (1R,2S,5R)-menthyl chloride (16052-42-9)

Conditions	Yield
With Lucas' reagent	91%

C22H34O7S (1082742-74-2) → (1R,2S,5R)-menthyl chloride (16052-42-9)

Conditions	Yield
With titanium tetrachloride In dichloromethane at -78℃; Inert atmosphere;	90%

menthyl tosylate (2230-82-2) → (1R,2S,5R)-menthyl chloride (16052-42-9)

Conditions	Yield
With titanium tetrachloride In dichloromethane at -78℃; Inert atmosphere;	90%
With chloro-trimethyl-silane; iron(III)-acetylacetonate In dichloromethane at 20℃; for 20h; Inert atmosphere;	75%

l-menthyl 8-quinolinesulfonate (117800-93-8) → (1R,2S,5R)-menthyl chloride (16052-42-9)

Conditions	Yield
With titanium tetrachloride In dichloromethane at -78℃; Inert atmosphere;	90%

(-)-menthol (2216-51-5) → (1R,2S,5R)-menthyl chloride (16052-42-9) + neomenthyl chloride (13371-12-5)

Conditions	Yield
With phosphorus pentachloride In pentane at -20℃; for 2.5h; Product distribution;	A 50% B 30%
With phosphorus pentachloride In pentane at -20℃; for 2.5h;	A 50% B 30%
With phosphorus pentachloride; iron(III) chloride In hexane at 0℃; for 1.5h; Title compound not separated from byproducts.;
With N-chloro-succinimide; para-thiocresol In dichloromethane Overall yield = 80 %Spectr.;	A n/a B n/a
Multi-step reaction with 3 steps 1.1: diethyl ether / 1.5 h / 0 - 23 °C / Inert atmosphere 1.2: 0 - 23 °C / Inert atmosphere 2.1: caesium carbonate / tetrahydrofuran; water / 0.17 h / 23 °C / Inert atmosphere 3.1: [4,4’-bis(1,1-dimethylethyl)-2,2’-bipyridine-N1,N1‘]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; Ethyl trichloroacetate / dichloromethane / 24 h / 27 °C / Inert atmosphere; Sealed tube; Irradiation View Scheme

2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)tetrahydro-2H-pyran (72020-06-5, 80924-03-4, 97526-56-2, 123121-06-2, 128946-28-1, 128946-29-2, 128946-30-5, 128946-31-6, 134052-28-1) → (1R,2S,5R)-menthyl chloride (16052-42-9) + neomenthyl chloride (13371-12-5) + (1R)-trans-p-menth-2-ene (5113-93-9)

Conditions	Yield
With dichloromethylenedimethyliminium chloride In acetonitrile at 0℃;	A 50 % Spectr. B 45 % Spectr. C 5 % Spectr.
With dichloromethylenedimethyliminium chloride In dichloromethane at 0℃;	A 18 % Spectr. B 42 % Spectr. C 40 % Spectr.

(1S,2S,4R)-2-bromo-1-isopropyl-4-methylcyclohexane (87161-57-7) → (1R,2S,5R)-menthyl chloride (16052-42-9) + neomenthyl chloride (13371-12-5)

Conditions	Yield
With bismuth(III) chloride In 1,2-dichloro-ethane for 2h; Heating;

(-)-menthol → (1R,2S,5R)-menthyl chloride (16052-42-9)

Conditions	Yield
With phosphorus pentachloride; iron(III) chloride; Petroleum ether Kuehlung;

(-)-menthol (2216-51-5) → (1R,2S,5R)-menthyl chloride (16052-42-9) + (1S,2R,4R)-2-bromo-1-isopropyl-4-methylcyclohexane

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 2: ferric(III) bromide; chloro-trimethyl-silane / dichloromethane / 0.17 h / 20 °C / Inert atmosphere View Scheme

(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl methanesulfonate (61548-81-0) → (1R,2S,5R)-menthyl chloride (16052-42-9) + (1S,2R,4R)-2-bromo-1-isopropyl-4-methylcyclohexane

Conditions	Yield
With ferric(III) bromide; chloro-trimethyl-silane In dichloromethane at 20℃; for 0.166667h; Inert atmosphere;

L-menthol chlorosulfite ester (1170718-78-1) + benzonitrile (100-47-0) → (1R,2S,5R)-menthyl chloride (16052-42-9) + (-)-N-((1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl)benzamide (1147723-25-8)

Conditions	Yield
With titanium(IV) fluoride In dichloromethane at 0℃; for 2h; Inert atmosphere;

(-)-menthol (2216-51-5) → (1R,2S,5R)-menthyl chloride (16052-42-9) + (-)-N-((1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl)benzamide (1147723-25-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / dichloromethane / 1 h / Inert atmosphere; Cooling with ice 2: titanium(IV) fluoride / dichloromethane / 2 h / 0 °C / Inert atmosphere View Scheme

L-menthol chlorosulfite ester (1170718-78-1) → (1R,2S,5R)-menthyl chloride (16052-42-9)

Conditions	Yield
With titanium tetrachloride In dichloromethane at 0℃; for 0.25h; Inert atmosphere;
With titanium tetrachloride at -78 - 0℃; for 1.25h; Catalytic behavior; Reagent/catalyst;

(-)-menthol (2216-51-5) → (1R,2S,5R)-menthyl chloride (16052-42-9) + neomenthyl chloride (13371-12-5) + (1S,3R)-1-(1-chloro-2-methylpropyl)-3-methylcyclopentane + (1S,3R)-1-(2-chloro-2-methylpropyl)-3-methylcyclopentane + dimenthyl sulfite (26510-92-9)

Conditions	Yield
With thionyl chloride In dichloromethane at 45℃; for 18h;

2-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-2-oxoacetic acid (70894-19-8) → (1R,2S,5R)-menthyl chloride (16052-42-9) + neomenthyl chloride (13371-12-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: caesium carbonate / tetrahydrofuran; water / 0.17 h / 23 °C / Inert atmosphere 2: [4,4’-bis(1,1-dimethylethyl)-2,2’-bipyridine-N1,N1‘]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; Ethyl trichloroacetate / dichloromethane / 24 h / 27 °C / Inert atmosphere; Sealed tube; Irradiation View Scheme

cesium 2-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-2-oxoacetate → (1R,2S,5R)-menthyl chloride (16052-42-9) + neomenthyl chloride (13371-12-5)

Conditions	Yield
With Ethyl trichloroacetate; [4,4’-bis(1,1-dimethylethyl)-2,2’-bipyridine-N1,N1‘]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate In dichloromethane at 27℃; for 24h; Inert atmosphere; Sealed tube; Irradiation; Overall yield = 50 %; Overall yield = 25.3 mg; stereoselective reaction;	A n/a B n/a

(1R,2S,5R)-menthyl chloride (16052-42-9) → (1R,2S,5R)-(-)menthylmagnesium chloride (63474-24-8)

Conditions	Yield
With ethyl bromide; magnesium In tetrahydrofuran 1.) 4 h, 50 degC, 2.) 1 h, 70 deg C;	95%

carbon dioxide (124-38-9) + (1R,2S,5R)-menthyl chloride (16052-42-9) → (-)-(1R,3R,4S)-4-isopropyl-1-methylcyclohexane-3-carboxylic acid (16052-40-7)

Conditions	Yield
Stage #1: (1R,2S,5R)-menthyl chloride With iodine; magnesium; ethylene dibromide at 70 - 75℃; for 4h; Inert atmosphere; Autoclave; Stage #2: carbon dioxide at 85 - 90℃; for 7.5h; Stage #3: With hydrogenchloride In water Temperature;	93%
With manganese; 2,9-dibutyl-3,4,7,8-tetramethyl-1,10-phenanthroline; NiBr2(monoglyme)2; lithium chloride In N,N-dimethyl-formamide under 760.051 Torr; Schlenk technique; Heating;	57%
Stage #1: carbon dioxide; (1R,2S,5R)-menthyl chloride With magnesium; iodine In tetrahydrofuran Stage #2: With hydrogenchloride In tetrahydrofuran; water Ice; Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages;	40%

(1R,2S,5R)-menthyl chloride (16052-42-9) + bis(pinacol)diborane (73183-34-3) → 2-((1R,2R,5R)-2-isopropyl-5-methylcyclohexyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1357000-40-8)

Conditions	Yield
With potassium tert-butylate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran at 20℃; for 92h; Inert atmosphere; Schlenk technique;	93%
With potassium tert-butylate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; copper(l) chloride In tetrahydrofuran at 20℃; for 48h; Inert atmosphere;	91%
With potassium tert-butylate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; copper(l) chloride In tetrahydrofuran at 20℃; for 31h; Inert atmosphere; optical yield given as %de; diastereoselective reaction;	85%

[platinum(II)dichloride(1,2-bis(diphenylphosphino)ethane)] (83095-83-4, 14647-25-7) + (1R,2S,5R)-menthyl chloride (16052-42-9) + magnesium (7439-95-4) + ethylene dibromide (106-93-4) → Pt(menthyl)(1,2-bis(diphenylphosphino)ethane)(bromide)

Conditions

Yield

In tetrahydrofuran (N2), Schlenk techniques; addn. of 1,2-dibromoethane to Mg in THF at 50°C, after 10 min addn. of menthyl chloride, heating under reflux for 5 h at 65°C, addn. to soln. of Au complex in THF, stirring for1 h at 50°C; cooling to room temp., addn. of satd. aq. NH4Cl, opening to air, extn. (CH2Cl2), drying (MgSO4), filtration (Celite), evapn. in vacuo, washing with petroleum ether, drying in vacuo, elem. anal.;

82%

(1R,2S,5R)-menthyl chloride (16052-42-9) + magnesium (7439-95-4) + triphenyltin chloride (639-58-7) → (1R,2S,5R)-menthyltriphenyltin

Conditions	Yield
With HCl; PPh3; tert-butylhydroperoxide In tetrahydrofuran byproducts: Ph3PO; stirring (room temp., 1.5 h), refluxing (30 min), HCl addn., extg. (CH2Cl2), drying (MgSO4), evapn. (vac.), hexane and CH2Cl2 addn., fitering Ph3P off, tBuOOH addn., stirring (15 min), H2O addn.; chromy. (SiO2, hexane / CH2Cl2 = 80 : 20); elem. anal.;	73%

(1R,2S,5R)-menthyl chloride (16052-42-9) + 2-iodo-4-methylaniline (29289-13-2) → C17H27N*ClH

Conditions	Yield
Stage #1: (1R,2S,5R)-menthyl chloride With magnesium In tetrahydrofuran; ethylene dibromide at 60℃; for 1h; Schlenk technique; Inert atmosphere; Reflux; Stage #2: With zinc(II) chloride In tetrahydrofuran at 20℃; Negishi Coupling; Schlenk technique; Inert atmosphere; Stage #3: 2-iodo-4-methylaniline diastereoselective reaction;	73%

(1R,2S,5R)-menthyl chloride (16052-42-9) + 2,6-diiodo-4-methylaniline (64662-57-3) → 2,6-bis[(1R,2S,5R)-menthyl]-4-methylaniline

Conditions

Yield

Stage #1: (1R,2S,5R)-menthyl chloride With magnesium In tetrahydrofuran at 60℃; for 1h; Negishi Coupling; Schlenk technique; Inert atmosphere; Reflux; Stage #2: With zinc(II) chloride In tetrahydrofuran at 20℃; Negishi Coupling; Inert atmosphere; Schlenk technique; Stage #3: 2,6-diiodo-4-methylaniline With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; bis(dibenzylideneacetone)-palladium(0) In tetrahydrofuran at 20℃; for 16h; Inert atmosphere; Schlenk technique;

73%

(triphenylphosphine)gold(I) chloride (14243-64-2) + (1R,2S,5R)-menthyl chloride (16052-42-9) + magnesium (7439-95-4) → Au(menthyl)(triphenylphosphine)

Conditions

Yield

With 1,2-dibromoethane In tetrahydrofuran (N2), Schlenk techniques; addn. of 1,2-dibromoethane to Mg in THF at 50°C, after 20 min addn. of menthyl chloride, heating under reflux for 5 h at 65°C, addn. to soln. of Au complex in THF, stirring for2 h; addn. of dilute H2SO4, opening to air, extn. (CH2Cl2), drying (MgSO4), treatment with charcoal, filtration (Celite), evapn. in vacuo, washing with petroleum ether, drying in vacuo, elem. anal.;

67%

(1R,2S,5R)-menthyl chloride (16052-42-9) + sodium diphenylphosphide (4376-01-6) → ((1S,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl)-diphenyl-phosphane (43077-29-8) + neomenthyldiphenylphosphine oxide (43077-30-1) + diphenylphosphane (829-85-6)

Conditions	Yield
With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran at 25 - 67℃; for 16h;	A 66% B 24% C 5%

(1R,2S,5R)-menthyl chloride (16052-42-9) + 2-iodo-4,6-dimethylaniline (4102-54-9) → 2-[(1R,2S,5R)-menthyl]-4,6-dimethylaniline

Conditions

Yield

Stage #1: (1R,2S,5R)-menthyl chloride With magnesium In tetrahydrofuran at 60℃; for 1h; Schlenk technique; Inert atmosphere; Reflux; Stage #2: With zinc(II) chloride In tetrahydrofuran at 20℃; Negishi Coupling; Inert atmosphere; Schlenk technique; Stage #3: 2-iodo-4,6-dimethylaniline With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; bis(dibenzylideneacetone)-palladium(0) In tetrahydrofuran at 20℃; for 18h; Inert atmosphere; Schlenk technique; diastereoselective reaction;

64%

carbon dioxide (124-38-9) + (1R,2S,5R)-menthyl chloride (16052-42-9) → (1S,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (70985-58-9) + (-)-(1R,3R,4S)-4-isopropyl-1-methylcyclohexane-3-carboxylic acid (16052-40-7)

Conditions	Yield
Stage #1: (1R,2S,5R)-menthyl chloride With magnesium In tetrahydrofuran at 50℃; for 2h; Stage #2: carbon dioxide In tetrahydrofuran at 20℃; Inert atmosphere; Schlenk technique;	A 7.6% B 60.2%

(1R,2S,5R)-menthyl chloride (16052-42-9) + diphenylphosphane (829-85-6) → ((1S,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl)-diphenyl-phosphane (43077-29-8)

Conditions	Yield
With cesium hydroxide; 4 Angstroem MS In N,N-dimethyl-formamide at 23℃; for 63h;	54%

(1R,2S,5R)-menthyl chloride (16052-42-9) + sodium diphenylphosphide (4376-01-6) → ((1S,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl)-diphenyl-phosphane (43077-29-8) + diphenylphosphane (829-85-6)

Conditions	Yield
With 15-crown-5 In tetrahydrofuran at 25 - 67℃; for 16h;	A 15% B 53%

(1R,2S,5R)-menthyltriphenyltin + (1R,2S,5R)-menthyl chloride (16052-42-9) + tin(IV) chloride (7646-78-8) + magnesium (7439-95-4) → ((C3H7C6H9CH3)3Sn)2

Conditions	Yield
With HCl In tetrahydrofuran; benzene refluxing (5 h), stirring (room temp., 16 h), HCl and H2O addn., extg. (ether), drying (MgSO4), evapn. (vac.); recrystn. (EtOH); elem. anal.;	50%

(1R,2S,5R)-menthyl chloride (16052-42-9) + diphenyltin(IV) dichloride (1135-99-5) → di(-)menthyldiphenyltin (182160-38-9, 916576-67-5, 250636-43-2)

Conditions	Yield
With magnesium In tetrahydrofuran Ar-atmosphere; treatment of menthyl chloride with Mg, dropwise addn. of Sn-compd. (0°C, over 1 h), stirring at room temp. for 48 h; dropwise addn. of water at 0°C, stirring for 30 min at room temp., ether addn., washing of org. layer (water), drying (MgSO4), solvent removal, distn. (150-180°C/0.01 Torr); elem. anal.;	49%

(1R,2S,5R)-menthyl chloride (16052-42-9) + dimethyltin dichloride (753-73-1) → di(-)menthyldimethyltin

Conditions	Yield
With magnesium In tetrahydrofuran Ar-atmosphere; treatment of menthyl chloride with Mg, dropwise addn. of Sn-compd. (0°C, over 1 h), stirring at room temp. for 48 h; dropwise addn. of water at 0°C, stirring for 30 min at room temp., drying (MgSO4), solvent removal, distn. (90°C/40 mbar); elem. anal.;	48.2%

carbon dioxide (124-38-9) + (1R,2S,5R)-menthyl chloride (16052-42-9) + α-bromoacetophenone (70-11-1) → 2-oxo-2-phenylethyl (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxylate (1537179-13-7) + 2-oxo-2-phenylethyl (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxylate (1537179-15-9) + 2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-2-oxoethyl benzoate (1537179-16-0)

Conditions	Yield
Stage #1: (1R,2S,5R)-menthyl chloride With chloro-trimethyl-silane; magnesium; ethylene dibromide In tetrahydrofuran at 70℃; for 3h; Inert atmosphere; Stage #2: carbon dioxide In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 70 - 80℃; for 2h; Inert atmosphere; Stage #3: α-bromoacetophenone In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 80℃; Inert atmosphere;	A 44% B 15% C 1%
Stage #1: (1R,2S,5R)-menthyl chloride With chloro-trimethyl-silane; magnesium; ethylene dibromide In tetrahydrofuran at 70℃; for 3h; Inert atmosphere; Stage #2: carbon dioxide In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 70 - 80℃; for 2h; Stage #3: α-bromoacetophenone In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 80℃;	A 44% B 15% C 1%

(1R,2S,5R)-menthyl chloride (16052-42-9) + 3-chloro-1,2-benzisothiazole 1,1-dioxide (567-19-1) → 3-[(1'R)-menthoxy]-1,2-benzisothiazole 1,1-dioxide (18715-95-2) + (-)-3-[(1'R)-1'-menthyl]-1,2-benzisothiazole 1,1-dioxide + (+)-3-[(1'S)-1'-menthyl]-1,2-benzisothiazole 1,1-dioxide

Conditions	Yield
Stage #1: (1R,2S,5R)-menthyl chloride With ethyl bromide; magnesium In tetrahydrofuran for 0.5h; Metallation; Heating; Stage #2: 3-chloro-1,2-benzisothiazole 1,1-dioxide In tetrahydrofuran at 0℃; Grignard reaction; Further stages.;	A 15% B 38% C 13%

(1R,2S,5R)-menthyl chloride (16052-42-9) → (1R)-menth-3-ene (619-52-3) + (+)-Menthyllithium (135637-19-3) + (2R,5S,2'S,5'R)-2,2'-Diisopropyl-5,5'-dimethyl-bicyclohexyl (3294-50-6)

Conditions	Yield
With lithium In pentane 1) 2h, reflux, 2) 48h;	A 15.6% B 37% C n/a

(1R,2S,5R)-menthyl chloride (16052-42-9) + 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (201733-56-4) → 2–((1R,2R,5R)–2–isopropyl–5–methylcyclohexyl)–5,5–dimethyl–1,3,2–dioxaborinane

Conditions	Yield
With potassium tert-butylate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; copper(l) chloride In tetrahydrofuran for 24h; Inert atmosphere;	28%

(1R,2S,5R)-menthyl chloride (16052-42-9) + lithium diphenylphosphide (65567-06-8, 4541-02-0) → ((1S,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl)-diphenyl-phosphane (43077-29-8)

Conditions	Yield
In tetrahydrofuran at 40℃; for 40h;	24%

(1R,2S,5R)-menthyl chloride (16052-42-9) + diphenyltin(IV) dichloride (1135-99-5) + magnesium (7439-95-4) → bis((1R,2S,5R)-menthyl)diphenyltin

Conditions	Yield
In tetrahydrofuran stirring (room temp., 44 h), H2O addn., extg. (ether), drying (MgSO4), evapn. (vac.); chromy. (SiO2, hexane / CH2Cl2 = 97 : 3), evapn.; elem. anal.;	22%

(1R,2S,5R)-menthyl chloride (16052-42-9) + sodium diphenylphosphide (4376-01-6) → ((1S,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl)-diphenyl-phosphane (43077-29-8)

Conditions	Yield
With 15-crown-5 In tetrahydrofuran at 25 - 67℃; for 16h;	15%

Upstream product

• 15356-60-2 (1S,2R,5S)-(+)-menthol 
• 2216-51-5 (-)-menthol 
• 72020-06-5 2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)tetrahydro-2H-pyran 
• 1082742-74-2 C₂₂H₃₄O₇S 
• 2230-82-2 menthyl tosylate 
• 117800-93-8 l-menthyl 8-quinolinesulfonate 
• 70894-19-8 2-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-2-oxoacetic acid 
• 77774-21-1 l-(-)-(Menthyloxy)triphenylphosphonium triflate 
• 1170718-78-1 L-menthol chlorosulfite ester 
• 100-47-0 benzonitrile 
• 87161-57-7 (1S,2S,4R)-2-bromo-1-isopropyl-4-methylcyclohexane 
• 61548-81-0 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl methanesulfonate 

Downstream Products

• 5113-93-9 (1R)-trans-p-menth-2-ene 
• 500-00-5 3-p-menthene 
• 619-52-3 (1R)-menth-3-ene 
• 70912-45-7 1-(Neomentylphenylphosphino)-2-diphenylphosphinoethan 
• 135637-19-3 (+)-Menthyllithium 
• 3294-50-6 (2R,5S,2'S,5'R)-2,2'-Diisopropyl-5,5'-dimethyl-bicyclohexyl 
• 63474-24-8 (1R,2S,5R)-(-)menthylmagnesium chloride 
• 43077-30-1 neomenthyldiphenylphosphine oxide 
• 43077-29-8 ((1S,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl)-diphenyl-phosphane 
• 204917-65-7 l-2-(2-menthyl)pyridine 
• 65440-73-5 (R_P)-(L-menthyl)methylphenylphosphine 

Relevant articles and documents

Discovery, characterisation, and utilisation of selenoxide-sulfonic acid salts: A new class of selenoxide-based oxidant and stable selenoxide equivalent

The preparation and characterisation of a novel class of salts of selenoxides with sulfonic acids are described. They are readily prepared by simple addition of the sulfonic acid to a solution of selenoxide, and removal of solvent. In most cases they are colourless crystalline solids and are considerably more stable than the parent selenoxides, allowing full characterisation and X-ray crystallographic analysis. They also efficiently oxidise sulfides to sulfoxides, with no overoxidation, and clean regeneration of selenide. Their structure has been confirmed by 1H NMR spectroscopy and X-ray crystallography.

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Synthesis, characterization and hplc analysis of the (1S,2S,5R)-diastereomer and the enantiomer of the clinical candidate ar-15512

AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1R,2S,5R), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis. In order to confirm that the desired configuration of AR-15512 does not change throughout the process and to discard the presence of the enantiomer in the final product due to possible contamination of the initial starting material, both the enantiomer of AR-15512 and the diastereomer at the C-1 were synthesized and fully characterized. In addition, the absolute configuration of the (1S,2S,5R)-diastereomer was determined by X-ray crystallographic analysis, and new HPLC methods were designed and developed for the identification of the two stereoisomers and their comparison with the clinical candidate AR-15512.

Enantiospecific Synthesis of ortho-Substituted 1,1-Diarylalkanes by a 1,2-Metalate Rearrangement/anti-SN2′ Elimination/Rearomatizing Allylic Suzuki–Miyaura Reaction Sequence

The one-pot sequential coupling of benzylamines, boronic esters, and aryl iodides has been investigated. In the presence of an N-activator, the boronate complex formed from an ortho-lithiated benzylamine and a boronic ester undergoes stereospecific 1,2-metalate rearrangement/anti-SN2′ elimination to form a dearomatized tertiary boronic ester. Treatment with an aryl iodide under palladium catalysis leads to rearomatizing γ-selective allylic Suzuki–Miyaura cross-coupling to generate 1,1-diarylalkanes. When enantioenriched α-substituted benzylamines are employed, the corresponding 1,1-diarylalkanes are formed with high stereospecificity.