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65472-88-0 Usage

Originator

Naftifine,Sandoz (Novartis)

Uses

Different sources of media describe the Uses of 65472-88-0 differently. You can refer to the following data:
1. Naftifine (Naftin) is a synthetic allylamine derivative topical antifungal agent that works by blocking squalene 2,3-epoxidase, resulting in increased cell membrane permeability and cell death. It is structurally and pharmacologically related to terbinafine. It also has some antiinflammatory properties that may be due to its ability to alter chemotaxis by polymorphonucleocytes. It is most effective against dermatophytes, moderately active against molds, and less active against yeasts, including C. albicans.
2. Naftifine is only permitted to be used externally and only superficially as a drug with a broad spectrum of action against dermatophytes and candida infections. According to the initial data, it exceeds the activity of econazole. Moreover, it does not have a locally irritating effect. It is believed that the fungicide activity of this drug is based on its ability to inhibit the fungal enzyme squalene epoxidase, thus lowering the concentration of ergosterol. The corresponding enzyme in mammals is inhibited significantly less. Synonyms of this drug are exoderil, naftin, and others.
3. (E)-Naftifine is an intermediate in synthesizing Naftifine N-Oxide (N213110), which is an impurity or metabolite of Naftifine Hydrochloride (N213100), an allylamine antifungal agent.

Definition

ChEBI: A tertiary amine in which the nitrogen is substituted by methyl, alpha-naphthylmethyl, and (1E)-cinnamyl groups. It is used (usually as its hydrochloride salt) for the treatment of fungal skin infections.

Indications

Naftifine (Naftin) is a synthetic allylamine derivative topical antifungal agent that works by blocking squalene 2,3-epoxidase, resulting in increased cell membrane permeability and cell death. It is structurally and pharmacologically related to terbinafine. It also has some antiinflammatory properties that may be due to its ability to alter chemotaxis by polymorphonucleocytes. It is most effective against dermatophytes, moderately active against molds, and less active against yeasts, including C. albicans.

Manufacturing Process

To a mixture of 1.42 g of methyl-(1-naphthylmethyl)amine hydrochloride, 2.89 g of sodium carbonate and 10 ml of dimethylformamide is added, at room temperature, 1.25 g of cinnamyl chloride, dropwise. After 18 hours stirring, at room temperature, the mixture is filtered and the filtrate is evaporated in vacuo. The residue is dissolved in toluene and, after drying over sodium sulphate, evaporated to obtain the trans-N-(cinnamylmethyl)-Nmethyl-(1-naphthylmethyl)amine compound, boiling point 162-167°C/0.015 Torr.The free base may be converted, with isopropanolic hydrogen chloride solution, into the hydrochloride form, melting point 177°C (from propanol).

Brand name

Naftin (Merz).

Therapeutic Function

Antifungal

Synthesis Reference(s)

Journal of Medicinal Chemistry, 29, p. 112, 1986 DOI: 10.1021/jm00151a019Tetrahedron Letters, 25, p. 2535, 1984 DOI: 10.1016/S0040-4039(01)81224-7

Pharmaceutical Applications

A topical antifungal used as a 1% cream for the treatment of dermatophytoses, including tinea pedis, tinea corporis and tinea cruris.

Clinical Use

Naftifine was the first allyl amine to be discovered and marketed. It is subject to extensive first-pass metabolism to be orally active and, consequently, is only available in topical preparations. The widest use of naftifine is against various tinea infections of the skin.

Synthesis

Naftifine, (E)-N-methyl-N-(3-phenyl-2-propenyl)-1-naphthalinmethanamine (35.3.1), is synthesized by alkylating N-methyl-(1-naphthylmethyl)-amine with cinnamyl chloride in the presence of sodium carbonate.

Check Digit Verification of cas no

The CAS Registry Mumber 65472-88-0 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 6,5,4,7 and 2 respectively; the second part has 2 digits, 8 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 65472-88:
(7*6)+(6*5)+(5*4)+(4*7)+(3*2)+(2*8)+(1*8)=150
150 % 10 = 0
So 65472-88-0 is a valid CAS Registry Number.
InChI:InChI=1/C21H21N.ClH/c1-22(16-8-11-18-9-3-2-4-10-18)17-20-14-7-13-19-12-5-6-15-21(19)20;/h2-15H,16-17H2,1H3;1H/b11-8+;

65472-88-0SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 12, 2017

Revision Date: Aug 12, 2017

1.Identification

1.1 GHS Product identifier

Product name naftifine

1.2 Other means of identification

Product number -
Other names N-cinnamyl-N-methylnaphthalen-1-ylmethanamine

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:65472-88-0 SDS

65472-88-0Synthetic route

formaldehyd
50-00-0

formaldehyd

(E)-N-(naphthalen-1-ylmethyl)-3-phenylprop-2-en-1-amine
92610-10-1

(E)-N-(naphthalen-1-ylmethyl)-3-phenylprop-2-en-1-amine

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
With sodium dihydrogen phosphate In 1,4-dioxane; water at 60℃; for 0.166667h;100%
With sodium dihydrogenphosphate In 1,4-dioxane at 60℃; for 0.333333h;91%
With sodium tetrahydroborate 1.) CH3OH, H2O, reflux, 30 min, 2.) CH3OH, H2O, RT, 3 h; Yield given. Multistep reaction;
N-methyl-1-naphthalenemethylamine
14489-75-9

N-methyl-1-naphthalenemethylamine

(2E)-3-phenyl-2-propen-1-ol
4407-36-7

(2E)-3-phenyl-2-propen-1-ol

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Pt(COD)Cl2; bis[2-(diphenylphosphino)phenyl] ether In 1,4-dioxane for 12h; Heating;98%
With 1,1'-bis-(diphenylphosphino)ferrocene; bis(η3-allyl-μ-chloropalladium(II)) In methanol at 20℃; for 12h; Temperature; Solvent; Inert atmosphere;96%
With 1,10-Phenanthroline; palladium diacetate In toluene at 100℃; for 17h; Inert atmosphere; Schlenk technique; regioselective reaction;83%
Stage #1: N-methyl-1-naphthalenemethylamine; (2E)-3-phenyl-2-propen-1-ol With manganese(IV) oxide; polymer-bound trimethyl ammonium cyanoborohydride In dichloromethane for 5h;
Stage #2: With acetic acid for 17h;
72%
With triscarbonyl‐(η4–3,4‐bis(4‐methoxyphenyl)‐2,5‐diphenylcyclopenta‐2,4‐dienone)iron In nitromethane; toluene at 130℃; for 24h; Schlenk technique; Inert atmosphere;61%
(E)-cinnamyl phenyl ether
16519-25-8

(E)-cinnamyl phenyl ether

N-methyl-1-naphthalenemethylamine
14489-75-9

N-methyl-1-naphthalenemethylamine

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
With bis(η3-allyl-μ-chloropalladium(II)); Methyl formate; potassium carbonate; bis[2-(diphenylphosphino)phenyl] ether In water at 20℃; for 0.333333h; chemoselective reaction;98%
(E)-3-phenylacrylic acid
140-10-3

(E)-3-phenylacrylic acid

N-methyl-1-naphthalenemethylamine
14489-75-9

N-methyl-1-naphthalenemethylamine

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
With potassium phosphate; 18-crown-6 ether; phenylsilane In tetrahydrofuran at 80℃; for 36h; Glovebox; Molecular sieve; Schlenk technique;96%
(E)-N-(naphthalen-1-ylmethyl)-3-phenylprop-2-en-1-amine
92610-10-1

(E)-N-(naphthalen-1-ylmethyl)-3-phenylprop-2-en-1-amine

acetonitrile
75-05-8

acetonitrile

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
With 18-crown-6 ether; carbon dioxide at 80℃; under 750.075 Torr; for 72h; Inert atmosphere; Schlenk technique; Glovebox;95%
(±)-3-(N-methyl-N-((naphthalen-5-yl)methyl)amino)-1-phenylpropan-1-ol
98977-94-7

(±)-3-(N-methyl-N-((naphthalen-5-yl)methyl)amino)-1-phenylpropan-1-ol

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
With hydrogenchloride In water Reflux;90%
With hydrogenchloride for 2h; Heating;
1-naphthalene methanol
4780-79-4

1-naphthalene methanol

(E)-N-methylcinnamylamine
60960-88-5, 93085-46-2, 83554-67-0

(E)-N-methylcinnamylamine

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Stage #1: 1-naphthalene methanol; (E)-N-methylcinnamylamine With manganese(IV) oxide; polymer-bound trimethyl ammonium cyanoborohydride In dichloromethane for 5h;
Stage #2: With acetic acid for 17h;
62%
bromobenzene
108-86-1

bromobenzene

N-methyl-1-naphthalenemethylamine
14489-75-9

N-methyl-1-naphthalenemethylamine

1-acetoxy-5-methyl-3,7-dioxo-9-vinyl-2,8-dioxa-5-aza-1-borabicyclo[3.3.1]nonan-5-ium-1-uide

1-acetoxy-5-methyl-3,7-dioxo-9-vinyl-2,8-dioxa-5-aza-1-borabicyclo[3.3.1]nonan-5-ium-1-uide

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
With potassium phosphate; bis(η3-allyl-μ-chloropalladium(II)); triphenylphosphine In tetrahydrofuran; water at 80℃; for 16h; Sealed tube; Inert atmosphere; Schlenk technique;62%
formaldehyd
50-00-0

formaldehyd

trans-2-phenylvinylboronic acid
6783-05-7

trans-2-phenylvinylboronic acid

N-methyl-1-naphthalenemethylamine
14489-75-9

N-methyl-1-naphthalenemethylamine

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Mechanism; multistep reaction; other substrates, other boronic acids; E-selectivity;
1) dioxane, 90 deg C, 10 min, 2) dioxane, 90 deg C, 10 min; Yield given. Multistep reaction;
(naphth-1-yl)methylamine
118-31-0

(naphth-1-yl)methylamine

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: manganese dioxide; NaBH4; 4A MS / CH2Cl2 / 17 h / Heating
1.2: 86 percent / MeOH / 0.67 h / 0 - 20 °C
2.1: 91 percent / NaH2PO4 / dioxane / 0.33 h / 60 °C
View Scheme
Multi-step reaction with 3 steps
1: benzene / Heating
2: 100 percent / NaBH4 / methanol / 0.33 h / 40 °C
3: 2.) NaBH4 / 1.) CH3OH, H2O, reflux, 30 min, 2.) CH3OH, H2O, RT, 3 h
View Scheme
Multi-step reaction with 3 steps
2: NaBH4
3: 100 percent / NaH2PO3 / H2O; dioxane / 0.17 h / 60 °C
View Scheme
Multi-step reaction with 2 steps
1.1: dichloro( 1,5-cyclooctadiene)platinum(ll); bis[2-(diphenylphosphino)phenyl] ether / 1,4-dioxane / 110 °C / Schlenk technique; Inert atmosphere
1.2: Schlenk technique; Inert atmosphere; Reflux
2.1: [1,3-bis(2,4,6-trimethylphenyl)imidazol]-2-ylidene; diphenylsilane / N,N-dimethyl-formamide / 48 h / 50 °C / 760.05 Torr
View Scheme
(2E)-3-phenyl-2-propen-1-ol
4407-36-7

(2E)-3-phenyl-2-propen-1-ol

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: manganese dioxide; NaBH4; 4A MS / CH2Cl2 / 17 h / Heating
1.2: 86 percent / MeOH / 0.67 h / 0 - 20 °C
2.1: 91 percent / NaH2PO4 / dioxane / 0.33 h / 60 °C
View Scheme
Multi-step reaction with 2 steps
1.1: dichloro( 1,5-cyclooctadiene)platinum(ll); bis[2-(diphenylphosphino)phenyl] ether / 1,4-dioxane / 110 °C / Schlenk technique; Inert atmosphere
1.2: Schlenk technique; Inert atmosphere; Reflux
2.1: [1,3-bis(2,4,6-trimethylphenyl)imidazol]-2-ylidene; diphenylsilane / N,N-dimethyl-formamide / 48 h / 50 °C / 760.05 Torr
View Scheme
Multi-step reaction with 3 steps
1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere
2: hydrazine hydrate / methanol / 20 °C / Inert atmosphere
3: 1,1'-bis-(diphenylphosphino)ferrocene; bis(η3-allyl-μ-chloropalladium(II)) / methanol / 12 h / 20 °C / Inert atmosphere
View Scheme
(E)-3-phenylpropenal
14371-10-9

(E)-3-phenylpropenal

yeast

yeast

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: benzene / Heating
2: 100 percent / NaBH4 / methanol / 0.33 h / 40 °C
3: 2.) NaBH4 / 1.) CH3OH, H2O, reflux, 30 min, 2.) CH3OH, H2O, RT, 3 h
View Scheme
N-methyl-1-naphthalenemethylamine
14489-75-9

N-methyl-1-naphthalenemethylamine

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 55 percent / aq. HCl / H2O; ethanol / 2 h / Heating
2: 100 percent / NaBH4 / methanol / 0.25 h / Ambient temperature
3: 5N aq. HCl / 2 h / Heating
View Scheme
Multi-step reaction with 2 steps
1: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere
2: bis(dibenzylideneacetone)-palladium(0); bathophenanthroline / N,N-dimethyl-formamide / 20 °C / Inert atmosphere
View Scheme
Multi-step reaction with 3 steps
1: SPGS-550M; potassium carbonate / water; toluene / 4 h / 20 °C
2: chloro[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]copper(I); SPGS-550M; sodium hydroxide / water / 2 h / 20 °C / Green chemistry
3: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate / water / 2 h / 80 °C / Green chemistry
View Scheme
Multi-step reaction with 3 steps
1: SPGS-550M; potassium carbonate / water; toluene / 4 h / 20 °C
2: chloro[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]copper(I); SPGS-550M; sodium hydroxide / water / 2 h / 20 °C / Green chemistry
3: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate / water / 2 h / 80 °C / Green chemistry
View Scheme
Multi-step reaction with 3 steps
1: triethylamine / 1,4-dioxane / Reflux
2: sodium tetrahydroborate / methanol / 0.5 h / 20 °C
3: hydrogenchloride / water / Reflux
View Scheme
3--1-phenyl-1-propanone
98977-93-6

3--1-phenyl-1-propanone

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 100 percent / NaBH4 / methanol / 0.25 h / Ambient temperature
2: 5N aq. HCl / 2 h / Heating
View Scheme
Multi-step reaction with 2 steps
1: sodium tetrahydroborate / methanol / 0.5 h / 20 °C
2: hydrogenchloride / water / Reflux
View Scheme
N-(3-phenyl-2-propenylidene)-1-naphthalenemethanamine
98977-78-7

N-(3-phenyl-2-propenylidene)-1-naphthalenemethanamine

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 100 percent / NaBH4 / methanol / 0.33 h / 40 °C
2: 2.) NaBH4 / 1.) CH3OH, H2O, reflux, 30 min, 2.) CH3OH, H2O, RT, 3 h
View Scheme
Multi-step reaction with 2 steps
1: NaBH4
2: 100 percent / NaH2PO3 / H2O; dioxane / 0.17 h / 60 °C
View Scheme
1-Chloromethylnaphthalene
86-52-2

1-Chloromethylnaphthalene

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: 78 percent / ethanol / Ambient temperature
2: 55 percent / aq. HCl / H2O; ethanol / 2 h / Heating
3: 100 percent / NaBH4 / methanol / 0.25 h / Ambient temperature
4: 5N aq. HCl / 2 h / Heating
View Scheme
Multi-step reaction with 4 steps
1: potassium carbonate / 24 h / 20 °C / Inert atmosphere
2: sodium hydroxide / diethyl ether; water / 0.5 h / 0 °C
3: tris-(dibenzylideneacetone)dipalladium(0); sodium acetate / benzonitrile / 1 h / 80 °C
4: lithium aluminium tetrahydride / tetrahydrofuran / 2.5 h / -78 - 60 °C / Inert atmosphere
View Scheme
(E)-3-phenylpropenal
14371-10-9

(E)-3-phenylpropenal

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Multi-step reaction with 3 steps
2: NaBH4
3: 100 percent / NaH2PO3 / H2O; dioxane / 0.17 h / 60 °C
View Scheme
N-(naphthalen-1-ylmethyl)prop-2-en-1-amine
134275-02-8

N-(naphthalen-1-ylmethyl)prop-2-en-1-amine

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: sodium hydroxide / diethyl ether; water / 0.5 h / 0 °C
2: tris-(dibenzylideneacetone)dipalladium(0); sodium acetate / benzonitrile / 1 h / 80 °C
3: lithium aluminium tetrahydride / tetrahydrofuran / 2.5 h / -78 - 60 °C / Inert atmosphere
View Scheme
methyl allyl(naphthalen-1-ylmethyl)carbamate
1334031-94-5

methyl allyl(naphthalen-1-ylmethyl)carbamate

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: tris-(dibenzylideneacetone)dipalladium(0); sodium acetate / benzonitrile / 1 h / 80 °C
2: lithium aluminium tetrahydride / tetrahydrofuran / 2.5 h / -78 - 60 °C / Inert atmosphere
View Scheme
bromobenzene
108-86-1

bromobenzene

(E)-N-methyl-N-(naphthalen-1-ylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-amine

(E)-N-methyl-N-(naphthalen-1-ylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-amine

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In water at 80℃; for 2h; Suzuki Coupling; Green chemistry;59 mg
iodobenzene
591-50-4

iodobenzene

(E)-N-methyl-N-(naphthalen-1-ylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-amine

(E)-N-methyl-N-(naphthalen-1-ylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-amine

naftifine
65472-88-0

naftifine

Conditions
ConditionsYield
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In water at 80℃; for 2h; Suzuki Coupling; Green chemistry;75 mg
naftifine
65472-88-0

naftifine

N-methyl-N-(3-phenylpropyl)-1-naphthalenemethanamine
98977-55-0

N-methyl-N-(3-phenylpropyl)-1-naphthalenemethanamine

Conditions
ConditionsYield
With tris(triphenylphosphine)rhodium(l) chloride; hydrogen In toluene at 70℃; for 24h; Inert atmosphere;83%
With Wilkinson's catalyst; hydrogen In toluene at 70℃; for 24h;83%
naftifine
65472-88-0

naftifine

C21H23NO2

C21H23NO2

Conditions
ConditionsYield
With osmium(VIII) oxide; 4-methylmorpholine N-oxide In water; acetone at 20℃; for 24h; Inert atmosphere;78%
naftifine
65472-88-0

naftifine

C21H23NO2

C21H23NO2

Conditions
ConditionsYield
With osmium(VIII) oxide; 4-methylmorpholine N-oxide In water; acetone at 20℃; for 24h; Inert atmosphere;78%
naftifine
65472-88-0

naftifine

C21H21NO

C21H21NO

Conditions
ConditionsYield
With sodium carbonate; 3-chloro-benzenecarboperoxoic acid In dichloromethane at -78℃; for 1h; Inert atmosphere;60%
With sodium carbonate; 3-chloro-benzenecarboperoxoic acid In dichloromethane at -78℃; for 1h; Inert atmosphere;60%

65472-88-0Relevant articles and documents

THE BORONIC ACID MANNICH REACTION: A NEW METHOD FOR THE SYNTHESIS OF GEOMETRICALLY PURE ALLYLAMINES

Petasis, Nicos A.,Akritopoulou, Irini

, p. 583 - 586 (1993)

Reaction of vinyl boronic acids with the adducts of secondary amines and paraformaldehyde gives tertiary allylamines with the same geometry.This simple and practical method was used for the synthesis of geometrically pure naftifine, a potent antifungal agent.

Amine compound as well as preparation method and application thereof

-

Paragraph 0077; 0083-0086, (2021/08/21)

The invention discloses an amine compound containing allyl or benzyl as well as a preparation method and application of the amine compound. The preparation method comprises the steps of sequentially adding a raw material 1, amine, a catalyst and an additive into a reaction solvent, and stirring and reacting for 12-24 hours in an air atmosphere at the temperature of 50-120 DEG C to obtain a reaction solution, wherein the raw material 1 is allyl alcohol or benzyl alcohol, and the molar volume ratio of the raw material 1 to the amine to the catalyst to the additive to the reaction solvent is (0.2 to 8) mmol: (0.4 to 12) mmol: (0.01 to 0.4) mmol: (0.01 to 0.4) mmol: (2 to 40) mL; and removing the reaction solvent of the reaction solution, and then carrying out purification through thin layer chromatography/column chromatography, wherein a developing solvent system is petroleum ether/ethyl acetate, and the amine compound containing allyl or benzyl is obtained. The amine compound can be applied to preparation of framework of biological and pharmaceutical active molecules. The preparation method disclosed by the invention is wide in applicable substrate range, convenient to operate, green and environment-friendly.

N -Butylpyrrolidone (NBP) as a non-toxic substitute for NMP in iron-catalyzed C(sp2)-C(sp3) cross-coupling of aryl chlorides

Bisz, Elwira,Koston, Martina,Szostak, Michal

supporting information, p. 7515 - 7521 (2021/10/12)

Although iron catalyzed cross-coupling reactions show extraordinary promise in reducing the environmental impact of more toxic and scarce transition metals, one of the main challenges is the use of reprotoxic NMP (NMP = N-methylpyrrolidone) as the key ligand to iron in the most successful protocols in this reactivity platform. Herein, we report that non-toxic and sustainable N-butylpyrrolidone (NBP) serves as a highly effective substitute for NMP in iron-catalyzed C(sp2)-C(sp3) cross-coupling of aryl chlorides with alkyl Grignard reagents. This challenging alkylation proceeds with organometallics bearing β-hydrogens with efficiency superseding or matching that of NMP with ample scope and broad functional group tolerance. Appealing applications are demonstrated in the cross-coupling in the presence of sensitive functional groups and the synthesis of several pharmaceutical intermediates, including a dual NK1/serotonin inhibitor, a fibrinolysis inhibitor and an antifungal agent. Considering that the iron/NMP system has emerged as one of the most powerful iron cross-coupling technologies available in both academic and industrial research, we anticipate that this method will be of broad interest.

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