Scope and limitations of auxiliary-assisted, palladium-catalyzed arylation and alkylation of sp2 and sp3 C-H bonds

Article

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Scope and Limitations of Auxiliary-Assisted, Palladium-Catalyzed

Arylation and Alkylation of sp²and sp³C−H Bonds

Enrico T. Nadres, Gerson Ivan Franco Santos,^†Dmitry Shabashov, and Olafs Daugulis*

Department of Chemistry, University of Houston, Houston, Texas 77204, United States

S

* Supporting Information

ABSTRACT: The scope of palladium-catalyzed, auxiliary-assisted

direct arylation and alkylation of sp²and sp³C−H bonds of amine

and carboxylic acid derivatives has been investigated. The method

employs a palladium acetate catalyst, substrate, aryl, alkyl, benzyl, or

allyl halide, and inorganic base in tert-amyl alcohol or water solvent at

100−140 °C. Aryl and alkyl iodides as well as benzyl and allyl

bromides are competent reagents in this transformation. The

picolinic acid auxiliary is used for amine γ-functionalization, and

the 8-aminoquinoline auxiliary is used for carboxylic acid β-functionalization. Some optimization of base, additives, and solvent is

required for achieving best results.

Scheme 1. Auxiliary-Assisted Arylation

1. INTRODUCTION

Transition-metal-catalyzed functionalization of carbon−hydro-

gen bonds is becoming an important synthetic tool that allows

eﬃcient creation of carbon−carbon bonds.¹Regioselective,

intermolecular arylation and alkylation of heterocycles and other

arenes can be eﬃciently accomplished by employing ﬁrst- and

second-row transition-metal catalysis.²A recent report by

Ackerman shows that meta-alkylation of 2-phenylpyridine

derivatives is feasible.^2lIn contrast, intermolecular functionaliza-

tion of unactivated (not benzylic or α to heteroatom) sp³C−H

bonds has attracted less attention.³Many of the published

examples of sp³C−H bond functionalization involve positions

adjacent to quaternary centers.^3a−fFewer reports deal with

functionalization of sp³C−H bonds in systems where β-hydride

elimination from metalated intermediates is possible. Ohno has

prepared indolines from N-alkyl-2-bromoanilines.³ⁱYu has

developed methods for palladium-catalyzed oleﬁnation, carbon-

ylation, and arylation of sp³C−H bonds by employing

perﬂuoroaniline auxiliaries and utilized pyridine as a directing

group in an example of sp³C−H bond alkylation by alkylboronic

acids.^3g−lSanford has reported an aerobic sp³C−H bond

oleﬁnation by using a pyridine directing group.^3mA direct Pd-

catalyzed γ-arylation of amino acid esters bearing a removable N-

(2-pyridyl)sulfonyl directing group has been described by

activation step. The electron-rich dianionic pincer-type ligand on

palladium facilitates oxidative addition of aryl halide to the Pd(II)

intermediate 1 and stabilizes the presumed high-valent Pd

intermediates.^4b,6We have also reported auxiliary-directed

synthesis of unnatural amino acids as well as picolinic acid-

directed heterocycle formation.^4c,dAminoquinoline and picolinic

acid can also direct copper-catalyzed carbon−heteroatom bond

formation.^4e−gSubsequently, several other groups have used

these auxiliaries for new reaction development and synthetic

purposes. Corey has used the 8-aminoquinoline auxiliary to

arylate sp³C−H bonds in amino acid derivatives.^5aChen has

employed 8-aminoquinoline auxiliary in the total synthesis of

celogentin C.^5bSynthesis of the Leu-Trp component of the

celogentin family of cyclic peptides via C−H bond functionaliza-

tion methodology has also been disclosed.^5cElegant total

Fernandez-Iban

́

ez.³ⁿ

̃

In 2005, we reported the β-arylation of carboxylic acid and γ-

arylation of amine derivatives by employing an 8-aminoquinoline

or picolinic acid auxiliary, catalytic Pd(OAc)₂, stoichiometric

AgOAc, and an aryl iodide coupling partner.^4aSubsequently, a

number of auxiliaries were investigated for carboxylic acid β-

arylation, and it was shown that silver salts can be replaced by

simple inorganic bases (Scheme 1).^4bOmission of silver allowed

catalytic alkylation of sp²and sp³C−H bonds. Functionalization

regiochemistry is determined by a double ﬁve-membered

palladacycle intermediate 1 that is formed in the C−H bond

Received: June 27, 2013

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Scheme 2. Auxiliary-Assisted, Palladium-Catalyzed Arylation and Alkylation of sp²and sp³C−H Bonds

a

syntheses of piperborenines and the proposed structure of

pipercyclobutanamide A by using 8-aminoquinoline and 2-

thiomethylaniline directing groups have been developed by

Baran.^5d,eCarbocycles have been constructed by using 8-

aminoquinoline directing group.^5fChen has employed picolinic

acid directing group for arylation, alkenylation, and alkylation of

sp²and sp³C−H bonds.^5g,h,l,mQuinolinecarboxylic acid

naphthylamide arylation has been recently disclosed.^3kPicolina-

mide and 8-aminoquinoline-directed alkynylation of sp²and sp³

C−H bonds has also been reported.^5i,jFurthermore, iron, nickel,

copper, and ruthenium catalysis has been used for 8-amino-

quinoline-containing carboxamide functionalization.^{4e−g,5n−q}

These examples show that monoanionic, chelating auxiliaries

have found wide applications for C−H to C−C bond conversion

in a variety of catalytic systems. Signiﬁcantly, application of these

auxiliaries in the construction of complex natural products shows

that C−H bond functionalization methodology has been

introduced into mainstream organic synthesis. Consequently,

further methodological and mechanistic investigations that

would increase the scope and understanding of C−H bond

functionalization processes are warranted. We report here the

scope and limitations of auxiliary-assisted, palladium-catalyzed

arylation and alkylation of sp²and sp³C−H bonds in amine and

carboxylic acid derivatives (Scheme 2).

Table 1. Arylation Optimization

entry

reaction conditions

conv (%)

1

2

3

4

5

6

K₃PO₄, toluene/CH₃CN, 140 °C, 16 h

Cs₂CO₃, toluene/CH₃CN, 140 °C, 16 h

CsOAc, toluene/CH₃CN, 140 °C, 16 h

CsOAc, tert-amyl alcohol, 140 °C, 24 h

CsOAc, 10% CuBr₂, tert-amyl alcohol, 110 °C, 24 h

CsOAc, 10% CuBr₂, tert-amyl alcohol, 140 °C, 24 h

15

30

90

b

75 (70)

b

>99 (99)

a

Conversion measured by GC with internal standard. See the

Experimental Section for details. Isolated yield.

b

iodoanisole gives 98% isolated yield if AgOAc is used and 73%

yield if CsOAc is employed (entry 6). 4-Bromophenylation of 1-

naphthylamine picolinamide aﬀords a nearly identical yield of

product in both cases (entry 10). However, AgOAc conditions

allow for a lower Pd(OAc)₂loading (2% vs 5% for CsOAc base).

Three large-scale reactions (entries 4, 11, and 12) aﬀorded

excellent product yields showing that scale-up to at least 50 mmol

is possible. Phenethylamine derivative is arylated in moderate

yield, presumably due to the requirement for a less favorable six-

membered palladacycle intermediate (entry 13). In contrast to

this result, our previous benzylamine arylation methodology is

not applicable to arylation of phenethylamines.⁸Alkenylation of

sp²C−H bonds is also possible, and benzylamine picolinamide

was reacted with iodostyrene to give coupling product in 86%

yield. The ester, chloro, bromo, ether, and triﬂuoromethyl

functionalities are compatible with the arylation conditions. The

reaction fails if aryl bromide coupling partners are used.

Benzylamine picolinamide was reacted with bromobenzene

under conditions of entry 2, and arylation product was not

detected in the reaction mixture.

Directing groups can be removed by using n-butylamine and

AlCl₃in toluene at 90 °C or NaOH in ethanol (Scheme 3).⁹Free

arylated amines are obtained in good to excellent yields.

Synthesis of even more hindered amines is possible. Acylation

of 8-(p-tolyl)-1-naphthylamine by propionyl chloride followed

by palladium-catalyzed arylation aﬀords 2-(4-carbethoxyphen-

yl)-8-(p-tolyl)-1-naphthylamine derivative in a good yield

(Scheme 4).¹⁰Recently, a method for 1-aminonaphthalene

quinolinecarboxamide arylation has been reported; however, it

requires use of 15 mol % of Pd(OAc)₂.^5k

2. RESULTS AND DISCUSSION

2.1. Picolinamide Arylation Optimization. Based on our

previous results with carboxylic acid derivative functionalization,

the initial optimization experiments were aimed at replacing

silver acetate with other stoichiometric additives for arylation of

cumylamine picolylamide (Table 1). Potassium phosphate and

cesium carbonate bases were ineﬃcient (entries 1 and 2). Better

results were obtained with cesium acetate in tert-amyl alcohol

(entry 4). Addition of 10 mol % of CuBr₂allowed us to achieve

full conversion to the diarylation product (entry 6). Thus, the

optimized arylation conditions include 4 equiv of CsOAc base in

tert-amyl alcohol solvent, 5 mol % of Pd(OAc)₂, 10 mol % CuBr₂,

and 4 equiv of ArI at 140 °C.

2.2. Benzylpicolinamide Arylation. The silver-free con-

ditions were applied to arylation of a number of benzylpicoli-

namides (Table 2). Benzylamine derivatives are arylated in

excellent yields (entries 1−3). Diarylated products are obtained

if unsubstituted benzylamines are employed (entries 1 and 2).

We are interested in the synthesis of 8-aryl-1-naphthylamines

that could be used in the synthesis of ligands for Brookhart-type

transition-metal catalyzed oleﬁn polymerization.⁷Consequently,

arylation of picolinamide of 1-naphthylamine was investigated in

depth (entries 4−12). The reaction is successful both by using

AgOAc base and by using CsOAc base. Thus, reaction with 4-

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Table 2. Arylation of Benzylpicolinamides

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Table 2. continued

a

For CsOAc base: 5 mol % of Pd(OAc)₂, 10 mol % of CuBr₂additive, 4 equiv of CsOAc, t-AmOH solvent, 4 equiv of ArI, 1 mmol scale. For AgOAc

base: 2 mol % of Pd(OAc)₂, 2 equiv of AgOAc, no solvent, 4 equiv of ArI, 0.5 mmol scale. Yields are isolated yields. See the Experimental Section for

b

c

d

e

f

details. CsOAc base. AgOAc base. 20 mmol scale, 1.5 equiv of AgOAc. 50 mmol scale, 2 equiv of ArI, 1.5 equiv of AgOAc. 35 mmol scale, 3

equiv of ArI, 1.5 equiv of AgOAc.

Scheme 3. Directing Group Removal

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Scheme 4. Introduction of Second Aryl Group

a

Table 3. Arylation of Alkyl Picolinamides

a

Palladium acetate (5 mol %), 10 mol % of CuBr₂additive, 4 equiv of CsOAc, tert-amyl alcohol solvent, 4 equiv of ArI, 1 mmol scale. Yields are

b

isolated yields. See the Experimental Section for details. Palladium acetate (10 mol %), 20 mol % of CuBr₂, and K₂CO₃base used. Monoarylation

product also isolated in 13% yield.

2.3. Arylation of Alkylpicolinamides. Arylation of

unactivated sp³C−H bonds can be accomplished by employing

conditions developed for sp²C−H bond functionalization

(Table 3). Comparison of the arylation yields for propyl (entry

1), sec-butyl (entry 2), and 2-(2-methylbutyl) derivatives (entry

3) shows that the reaction is most eﬃcient for the substrates

possessing the most α-methyl groups. The increase in yield is

likely due to the Thorpe−Ingold eﬀect.¹¹Arylation of secondary

aliphatic C−H bonds is also feasible and proceeds in good yield

(entry 4). An amide derived from tert-octylamine was arylated in

modest yield. A mixture of mono- and diarylation products was

obtained, with functionalization occurring at the δ-positions

(entry 5). A six-membered palladacycle intermediate may be

responsible for less eﬃcient arylation. 2-Iodotoluene was

unreactive in all reactions tested as shown before for arylations

proceeding via high-valent palladium intermediates.^4a,b,10

2.4. Picolinamide Alkylation. The alkylation of picolina-

mide C−H bonds is presented in Table 4. Short optimization

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Table 4. Alkylation of Aryl- And Alkylpicolinamides

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Table 4. continued

a

Picolinamide (1 mmol), RI (4 mmol), Pd(OAc)₂(10 mol %), CuBr₂(20 mol %), K₂CO₃(4 mmol), H₂O solvent, 24 h at 120 °C. Yields are

b

c

d

isolated yields. See the Experimental Section for details. Palladium acetate (5 mol %), CuBr₂(10 mol %). 6 equiv of RI. Monoalkylation product

also isolated (14%). Dialkylation product also isolated (11%). tert-Amyl alcohol solvent, CsOAc base, 140 °C. Pivalic acid additive, tert-amyl

e

f

g

alcohol solvent, 110 °C.

showed that the best results are obtained by employing

potassium carbonate base in conjunction with water solvent. α-

Methylbenzylamine derivatives can be alkylated by various alkyl

iodides such as butyl iodide (entry 1), 4,4,4-triﬂuorobutyl iodide

(entry 2), isobutyl iodide (entry 3), and 2-phenethyl iodide

(entry 4) in good yields. However, if butyl iodide was replaced

with butyl bromide, no product was obtained. Benzylation can be

performed by employing benzyl iodide (entry 5). α,α-

Dimethylbenzylamine picolinamide reaction with n-butyl iodide

gave the dialkylation product in a good yield (entry 6).

Unexpectedly, secondary alkyl iodides are also reactive. Cyclo-

hexylation of benzyl picolinamide aﬀords a 20% yield of

monoalkylation product in addition to 14% of dialkylation

(entry 7). Similarly, alkylation of a 2-methoxybenzylamine

derivative gives the product in 14% yield (entry 8). 1-

Naphthylamine derivative is alkylated by n-octyl iodide in

moderate yield (entry 9). The alkylation of unactivated sp³C−H

bonds is ineﬃcient. Reaction of picolinic acid 2-(2-methyl)-

butylamide with n-amyl iodide yielded only 27% of the product

(entry 10). Chen has recently reported a method for

picolinamide sp³C−H bond alkylation.^5lWe have previously

shown that α-methylbenzylamines do not racemize under

palladium-catalyzed arylation conditions.⁸

substrate with alkyl iodide or benzyl bromide to 100−110 °C in

tert-amyl alcohol in the presence of K₂CO₃base and a catalytic

amount of pivalic acid. We have previously reported three

examples of 8-aminoquinoline benzamide alkylation.^4bTable 5

shows the alkylation scope and functional group tolerance.

Benzylation of alkoxy- (entries 1, 5, and 6), bromo- (entry 2), and

triﬂuoromethyl-substituted (entry 4) benzoic acid amides occurs

with good to excellent yields. The reaction cleanly aﬀords

dialkylation products if benzamide is substituted at the 4-position

or possesses a small substituent at the 3-position (entry 6). The

alkylation of 4-tert-butylbenzoic acid derivative can be

accomplished by employing ethyl iodide (entry 7), isobutyl

iodide (entry 8), 2-phenethyl iodide (entry 9), and ethyl-7-

iodoheptanoate (entry 10). Phthaloyl-protected 6-amino-1-

iodohexane is also reactive (entry 15). Furthermore, a variety

of benzyl bromides can be employed in the alkylation. Thus, the

reaction is successful with benzyl bromides possessing chloro

(entry 11), ester (entry 12), triﬂuoromethoxy (entry 13), and

nitro (entry 14) substituents, attesting to the functional group

tolerance of C−H bond alkylation methodology. Allylation is

also possible by employing 1-bromo-3-methylbut-2-ene,

although the isolated yield of the product is low (entry 16).

2.6. Alkylation of 8-Aminoquinoline Amide sp³C−H

Bonds. We have previously determined that the optimal

auxiliary for carboxamide C−H bond alkylation is 8-amino-

quinoline. Two examples of 8-aminoquinoline propionylamide

β-alkylation were published.^4bAlkylation conditions involve

heating the substrate with 5% Pd(OAc)₂and alkyl iodide or

benzyl bromide to 100−110 °C in tert-amyl alcohol in the

presence of K₂CO₃base and a catalytic amount of pivalic acid

(Table 6). 8-Aminoquinoline propionamide can be alkylated

with simple alkyl iodides such as ethyl (entry 1), butyl (entry 2),

2.5. Alkylation of 8-Aminoquinoline Benzamides. Our

initial conditions reported in 2005 that use of AgOAc for iodide

removal were not successful for C−H bond alkylation. Silver

acetate reacts with alkyl iodides competing with C-alkylation.

The new silver-free conditions, developed in 2010, are successful

since the competitive destruction of alkyl iodides is slow.^4bWe

have determined that the optimal auxiliary for C−H bond

alkylation of benzamide derivatives is 8-aminoquinoline. As

reported previously, alkylation conditions involve heating of the

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Table 5. Alkylation of 8-Aminoquinoline Benzamides

H

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Table 5. continued

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Table 5. continued

a

Pd(OAc)₂(5 mol %), K₂CO₃(2.5 equiv), substrate (0.74 mmol), pivalic acid (20 mol %), alkyl bromide or iodide (3−4 equiv), tert-amyl-OH

solvent, 12−96 h at 100−110 °C. Yields are isolated yields. See the Experimental Section for details.

octyl (entry 3), and phenethyl iodide (entry 4). Allylation by 1-

bromo-3-methylbut-2-ene is also possible, aﬀording the product

in a low yield (entry 5). Isobutyl iodide is reactive, and the

alkylation proceeds in good yield (entry 6). Benzylation with 2-

bromobenzyl bromide is successful, and the product is obtained

in 60% yield (entry 7). 2-Methylbutyric acid derivative is

selectively alkylated in the β-methyl group (entry 8).

Flurbiprofen¹²amide can also be alkylated in a moderate yield

(entry 9). Finally, alkylation of a secondary C−H bond proceeds

in a low yield (entry 10).

4. EXPERIMENTAL SECTION

General Considerations. Flash chromatography was performed on

60 Å silica gel. Preparative TLC was performed on TLC plates, 20 × 20

cm, 2000 μm thick, with ﬂuorescent indicator. GC analyses were

performed on a Restek column (Rtx-5, 15 m, 0.25 mm i.d.). Residual

solvent peaks were used as reference in ¹H NMR and ¹³C NMR spectra.

Melting points are uncorrected. The following starting materials were

obtained from commercial sources and were used without further

puriﬁcation: picolinic acid, triethylamine, dichloromethane, ethyl

chloroformate, MgSO₄, hexanes, ethyl acetate, cumylamine, α-

methylbenzylamine, benzylamine, 1-naphthylamine, pyridine, triphe-

nylphosphite, H₂SO₄, 2-methoxybenzylamine, 3,4-dimethoxyphene-

thylamine, tert-pentylamine, 2-aminobutane, 1-propylamine, cyclohexyl-

amine, tert-butylamine, palladium(II) acetate, copper(II) bromide,

cesium acetate, tert-amyl alcohol, iodo-4-methylbenzene, iodobenzene,

1-iodo-4-methoxybenzene, 1-bromo-4-iodobenzene, ethyl 4-iodoben-

zoate, iodoethane, 1,1,1-triﬂuoro-4-iodobutane, 1-iodo-2-methylpro-

pane, (2-iodoethyl)benzene, benzyl bromide, octyl iodide, iodobutane,

iodocyclohexane, iodopentane, aluminum chloride. Mass spectra were

performed on a Micromass Ultima Magnetic Sector.

Synthesis of Starting Materials. General Procedure for the

Preparation of the Picolinamides from Amines.¹³Picolinic acid (35

mmol, 4.3 g) and triethylamine (70 mmol, 9.70 mL) were dissolved in

dry dichloromethane (80 mL). The solution was cooled to 0 °C

followed by addition of ethyl chloroformate (35 mmol, 3.30 mL). The

mixture was subsequently stirred for 30 min in an ice bath. The amine

(20 mmol) was added dropwise via a syringe, and the suspension was

stirred for 1 h. The solution was warmed to room temperature and

stirred for 24 h. After that, water (100 mL) was added to the reaction

mixture, and the layers were separated. The aqueous layer was extracted

with dichloromethane (2 × 100 mL). The organic layers were

3. SUMMARY

In this paper, we report the scope and limitations of auxiliary-

assisted, palladium-catalyzed arylation and alkylation of sp²and

sp³C−H bonds in amine and carboxylic acid derivatives. The

method employs a palladium acetate catalyst, substrate, aryl,

alkyl, benzyl, or allyl halide, and inorganic base in tert-amyl

alcohol or water solvent at 100−140 °C. Aryl and alkyl iodides as

well as benzyl and allyl bromides are competent reagents in this

transformation. The picolinic acid auxiliary is used for amine γ-

functionalization, and the 8-aminoquinoline auxiliary is used for

carboxylic acid β-functionalization. Some optimization of base,

additives, and solvent is required for achieving best results. The

arylation is possible for both secondary and primary sp³C−H

bonds; however, alkylation of secondary sp³C−H bonds in

aminoquinoline derivatives and primary C−H bonds in

picolinamides is low yielding.

J

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Table 6. Alkylation of 8-Aminoquinoline Amide sp³C−H Bonds

K

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Table 6. continued

a

Pd(OAc)₂(5 mol %), K₂CO₃(2.5 equiv), substrate (0.74 mmol), pivalic acid (2 equiv), alkyl bromide or iodide (4 equiv), tert-amyl alcohol solvent,

24 h at 110 °C. Yields are isolated yields. See the Experimental Section for details.

combined, dried with MgSO₄, and concentrated. The residue was

puriﬁed by a silica gel column chromatography using hexanes/ethyl

acetate eluent.

N-Benzylpicolinamide (SM03). Picolinic acid (35 mmol, 4.3 g),

triethylamine (70 mmol, 9.70 mL), dichloromethane (80 mL), ethyl

chloroformate (35 mmol, 3.30 mL), and benzylamine (20 mmol, 2.18

mL). After chromatography (hexanes/ethyl acetate 60/40), white

N-(2-Phenylpropan-2-yl)picolinamide (SM01). Picolinic acid (35

crystals were obtained (3.81 g, 90%): R_f= 0.36 (hexanes/ethyl acetate

60/40). This compound is known.¹⁵¹H NMR (400 MHz, CDCl₃, ppm)

δ 8.53−8.51 (m, 1H), 8.37 (br s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.87−

7.83 (m, 1H), 7.43−7.40 (m, 1H), 7.38−7.32 (m, 4H), 7.30−7.26 (m,

1H), 4.67 (d, J = 6.0 Hz, 2H).

mmol, 4.3 g), triethylamine (70 mmol, 9.70 mL), dichloromethane (80

mL), ethyl chloroformate (35 mmol, 3.30 mL), and cumylamine (20

mmol, 2.7 g). After chromatography (hexanes/ethyl acetate 70/30),

white crystalline material was obtained (4.44 g, 93%): R_f= 0.40

1

(hexanes/ethyl acetate 70/30), mp = 87−88 °C (hexanes); H NMR

(400 MHz, CDCl₃, ppm) δ 8.55−8.54 (m, 1H), 8.48 (br s, 1H), 8.15−

8.13 (m, 1H), 7.84−7.80 (m, 1H), 7.48−7.45 (m, 2H), 7.44−7.40 (m,

1H), 7.36−7.31 (m, 2H), 7.25−7.21 (m, 1H), 1.85 (s, 6H); ¹³C NMR

(100 MHz, CDCl₃, ppm) δ 163.3, 150.6, 147.9, 146.9, 137.5, 128.5,

126.8, 126.1, 124.9, 122.0, 55.7, 29.3; FT-IR (neat, cm⁻¹) ν 3381, 1682,

15.13, 1570, 1436, 1384, 1365, 1280. Anal. Calcd for C₁₅H₁₆N₂O

(240.30 g/mol): C, 74.97; H, 6.71; N, 11.66. Found: C, 75.02; H, 6.71;

N, 11.62.

N-(Naphthalen-1-yl)picolinamide (SM04, 3). 1-Naphthylamine (7.2

g, 50 mmol) in pyridine (10 mL) was added dropwise in 15 min to a

stirred solution of picolinic acid (6.2 g, 50 mmol) in pyridine (14 mL) at

50 °C. Triphenyl phosphite (13 mL, 50 mmol) was added to the

resulting mixture followed by stirring at 110 °C for 4 h. The mixture was

cooled to room temperature followed by addition of distilled water (50

mL) and dichloromethane (50 mL). The mixture was placed in a 500

mL Erlenmeyer ﬂask, and aqueous H₂SO₄(150 mL; concentrated

H₂SO₄/water 1/1 v/v) was added. The mixture was shaken, and the

layers were separated. The organic layer was washed with aqueous

H₂SO₄(2 × 100 mL). The acidic aqueous layers were combined and

neutralized with solid sodium bicarbonate. The tan solids formed were

ﬁltered, washed thoroughly with distilled water, and then recrystallized

from methanol to aﬀord tan needles (10.9 g, 87%); this compound is

known;¹⁶¹H NMR (400 MHz, CDCl₃, ppm) δ 10.77 (s, 1H), 8.70 (d, J

= 8.2 Hz, 1 H), 8.36 (d, J = 8.2 Hz, 1 H), 8.36 (d, J = 7.8 Hz, 1 H), 8.09

(d, J = 8.2 Hz, 1 H), 7.95−7.88 (m, 2 H), 7.70 (d, J = 8.2 Hz, 1 H), 7.61−

7.50 (m, 4H).

N-(1-Phenylethyl)picolinamide (SM02, 11). Picolinic acid (35

mmol, 4.3 g), triethylamine (70 mmol, 9.70 mL), dichloromethane

(80 mL), ethyl chloroformate (35 mmol, 3.30 mL), and α-

methylbenzylamine (20 mmol, 2.60 mL). After chromatography

(hexanes/ethyl acetate 70/30), white crystals were obtained (4.35 g,

96%): R_f= 0.31 (hexanes/ethyl acetate 70/30); this compound is

known;¹⁴¹H NMR (400 MHz, CDCl₃, ppm) δ 8.54−8.52 (m, 1H), 8.32

(d, J = 6.3, 1H), 8.20−8.18 (m, 1H), 7.84−7.80 (m, 1H), 7.41−7.38 (m,

3H), 7.36−7.31 (m, 2H), 7.28−7.23 (m, 1H), 5.38−5.26 (m, 1H), 1.62

(d, J = 6.9 Hz, 3H).

L

dx.doi.org/10.1021/jo4013628 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

N-Propylpicolinamide (SM09). Picolinic acid (35 mmol, 4.3 g),

triethylamine (70 mmol, 9.70 mL), dichloromethane (80 mL), ethyl

chloroformate (35 mmol, 3.3 mL), and 1-propylamine (20 mmol, 1.64

mL). After chromatography (hexanes/ethyl acetate 70/30), colorless

liquid was obtained (3.11 g, 95%): R_f= 0.31 (hexanes/ethyl acetate 70/

30); this compound is known;^4a¹H NMR (400 MHz, CDCl₃, ppm) δ

8.55−8.53 (m, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.15 (br s, 1H), 7.86−7.82

(m, 1H), 7.35−7.40 (m, 1H), 3.46 (q, J = 6.4 Hz, 2H), 1.71−1.64 (m,

2H), 0.99 (t, J = 7.3 Hz, 3H).

N-(2-Methoxybenzyl)picolinamide (SM05). Picolinic acid (35

mmol, 4.3 g), triethylamine (70 mmol, 9.70 mL), dichloromethane

(80 mL), ethyl chloroformate (35 mmol, 3.30 mL), and 2-

methoxybenzylamine (20 mmol, 2.74 g). After chromatography

(hexanes/ethyl acetate 60/40), white powder was obtained (3.2 g,

71%): R_f= 0.34 (hexanes/ethyl acetate 60/40); this compound is

known;¹⁷¹H NMR (400 MHz, CDCl₃, ppm) δ 8.53−8.52 (m, 1H), 8.45

(br s, 1H), 8.21−8.19 (m, 1H), 7.85−7.77 (m, 1H), 7.35 (dd, J = 7.45,

1.7 Hz, 2H), 7.27−7.24 (m, 2H), 6.93−6.88 (m, 2H), 4.67 (d, J = 6.3 Hz,

2H), 3.88 (s, 3H).

N-Cyclohexylpicolinamide (SM10). Picolinic acid (35 mmol, 4.3 g),

triethylamine (70 mmol, 9.70 mL), dichloromethane (80 mL), ethyl

chloroformate (35 mmol, 3.3 mL), and cyclohexylamine (20 mmol, 2.29

mL). After chromatography (hexanes/ethyl acetate 70/30), white

needles were obtained (4.30 g, 98%): R_f= 0.32 (hexanes/ethyl acetate

70/30); this compound is known;¹⁹¹H NMR (400 MHz, CDCl₃, ppm)

δ 8.55−8.53 (m, 1H), 8.22−8.20 (m, 1H), 7.96 (s, J = 3.7 Hz, 1H),

7.86−7.82 (m, 1H), 7.43−7.40 (m, 1H), 4.01−3.94 (m, 1H), 2.04−2.00

(m, 2H), 1.80−1.75 (m, 2H), 1.68−1.63 (m, 1H), 1.49−1.19 (m, 5H).

N-(3,4-Dimethoxyphenethyl)picolinamide (SM06). Picolinic acid

(35 mmol, 4.3 g), triethylamine (70 mmol, 9.7 mL), dichloromethane

(80 mL), ethyl chloroformate (35 mmol, 3.3 mL), and 3,4-

dimethoxyphenethylamine (20 mmol, 3.4 mL). After chromatography

(hexanes/ethyl acetate 60/40), white powder was obtained (5.56 g,

97%): R_f= 0.30 (hexanes/ethyl acetate 60/40); this compound is

known;¹⁸¹H NMR (400 MHz, CDCl₃, ppm) δ 8.52−8.51 (m, 1H),

8.21−8.16 (m, 2H), 7.87−7.82 (m, 1H), 7.43−7.39 (m, 1H), 6.84−6.78

(m, 3H), 3.87−3.85 (m, 6H), 3.74−3.69 (m, 2H), 2.91−2.87 (m, 2H).

N-(2,4,4-Trimethylpentan-2-yl)picolinamide (SM11). Picolinic acid

(35 mmol, 4.3 g), triethylamine (70 mmol, 9.7 mL), dichloromethane

(80 mL), ethyl chloroformate (35 mmol, 3.3 mL), and tert-octylamine

(20 mmol, 3.2 mL). After column chromatography (hexanes/ethyl

acetate 70/30), a colorless oil was obtained (3.2 g, 62%): R_f= 0.56

1

(hexanes/ethyl acetate 70/30). H NMR (400 MHz, CDCl₃, ppm) δ

N-(tert-Pentyl)picolinamide (SM07). Picolinic acid (35 mmol, 4.3 g),

triethylamine (70 mmol, 9.70 mL), dichloromethane (80 mL), ethyl

chloroformate (35 mmol, 3.3 mL), and tert-pentylamine (20 mmol, 2.19

mL). After chromatography (hexanes/ethyl acetate 70/30), colorless

liquid was obtained (3.77 g, 98%): R_f= 0.55 (hexanes/ethyl acetate 70/

30); this compound is known;^5l¹H NMR (400 MHz, CDCl₃, ppm) δ

8.52−8.51 (m, 1H), 8.19−8.16 (m, 1H), 7.97 (br s, 1H), 7.85−7.81 (m,

1H), 7.41−7.38 (m, 1H), 1.87 (q, J = 7.3 Hz, 2H), 1.45 (s, 6H), 0.92 (t, J

= 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 163.4, 150.8,

147.8, 137.4, 125.9, 121.7, 53.7, 33.0, 26.4, 8.5.

8.52 (d, J = 4.0 Hz, 1H), 8.18 (d, J = 8.0, Hz, 1H), 8.12 (br s, 1H), 7.84−

7.81 (m, 1H), 7.40−7.38 (m, 1H), 1.87 (s, 2H), 1.56 (s, 6H), 1.03 (s,

9H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 163.1, 151.0, 148.9, 137.4,

125.8, 121.7, 54.7, 52.0, 31.8, 31.6, 29.2; FT-IR (neat, cm⁻¹) ν 2956,

1681, 1522, 1464, 1432, 1365, 1228. Anal. Calcd for C₁₄H₂₂N₂O (234.34

g/mol): C, 71.76; H, 9.46; N, 11.95. Found: C, 71.46; H, 9.29; N, 11.86.

General Procedure for the Preparation of the 8-Aminoquinoline

Amides. A round-bottom ﬂask was charged with 8-aminoquinoline and

triethylamine in dichloromethane. The respective benzoyl chloride was

added as a solution in dichloromethane (35 mL). The mixture was

stirred overnight at room temperature. The reaction mixture was

transferred into separatory funnel and washed with water (2 × 35 mL).

The water layer was extracted with dichloromethane (3 × 30 mL). The

organic layers were combined, washed with saturated aqueous NaHCO₃

(30 mL), and dried over MgSO₄. Filtration and evaporation under

reduced pressure gave the product. Amides not reported are known.^4b

N-(sec-Butyl)picolinamide (SM08). Picolinic acid (35 mmol, 4.3 g),

triethylamine (70 mmol, 9.70 mL), dichloromethane (80 mL), ethyl

chloroformate (35 mmol, 3.3 mL), and 2-aminobutane (20 mmol, 2.01

mL). After chromatography (hexanes/ethyl acetate 70/30), white

powder was obtained (3.27 g, 92%): R_f= 0.35 (hexanes/ethyl acetate

70/30); this compound is known;^4a¹H NMR (400 MHz, CDCl₃, ppm)

δ 8.56−8.55 (m, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.87−7.83 (m, 2H),

7.35−7.40 (m, 1H), 4.15−4.08 (m, 1H), 1.65−1.58 (m, 2H), 1.26 (d, J =

6.4 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H).

M

dx.doi.org/10.1021/jo4013628 | J. Org. Chem. XXXX, XXX, XXX−XXX

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a

Table 7. Optimization of Picolinamide Arylation

entry

reaction conditions

% GC yield (isolated)

1

4 equiv of NaOAc, 2 mL of MeCN, 60 °C, 16 h

0

2

4 equiv of NaOAc, 2 mL of toluene, 140 °C, 16 h

10

3

4 equiv of CsOAc, 1.6 mL of toluene, 0.4 mL of MeCN, 140 °C, 16 h

2 equiv of K₃PO₄, 1.6 mL of toluene, 0.4 mL of MeCN, 140 °C, 16 h

2 equiv of Cs₂CO₃, 1.6 mL of toluene, 0.4 mL of MeCN, 140 °C, 16 h

3 equiv of K₃PO₄, 1.6 mL of tert-amyl alcohol, 0.4 mL of H₂O, 90 °C, 16 h

3 equiv of K₂CO₃, 2 mL of tert-amyl alcohol, 90 °C, 20 h

30

4

15

5

15

6

70

7

80

8

4 equiv of K₂CO₃, 2 mL of tert-amyl alcohol, 110 °C, 24 h

4 equiv of K₂CO₃, 2 mL of tert-amyl alcohol, 140 °C, 24 h

4 equiv of CsOAc, 1 mL of tert-amyl alcohol, 110 °C, 24 h

4 equiv of CsOAc, 1 mL of tert-amyl alcohol, 140 °C, 24 h

10% CuBr₂, 4 equiv of CsOAc, 1 mL of tert-amyl alcohol, 110 °C, 24 h

10% CuBr₂, 4 equiv of CsOAc, 1 mL of tert-amyl alcohol, 140 °C, 24 h

90 (86)

80

9

10

11

12

13

85

90

75 (70)

99 (99)

a

Dodecane as internal standard; amide (0.5 mmol), ArI (4 mmol).

4-tert-Butyl-N-(quinolin-8-yl)benzamide (SM12, 12). 8-Amino-

quinoline (13.1 mmol, 1.9 g) and Et₃N (15.8 mmol, 2.2 mL) in

dichloromethane (35 mL), followed by 4-tert-butylbenzoyl chloride

(13.1 mmol, 2.6 g) in dichloromethane (25 mL). The mixture was

stirred for 24 h at room temperature. After chromatography (hexanes/

ethyl acetate 7/1), tan crystalline compound (6.92 g, 99% yield) was

obtained: R_f= 0.33 (hexanes/ethyl acetate 7/1), mp = 93−94 °C

(hexanes); ¹H NMR (500 MHz, CDCl₃, ppm) δ 10.73 (s, 1H), 8.95 (dd,

J = 7.4, 1.1 Hz, 1H), 8.85 (dd, J = 4.3, 1.6 Hz, 1H), 8.19 (dd, J = 8.3, 1.4

Hz, 1H), 8.05−8.01 (m, 2H), 7.62−7.52 (m, 4H), 7.50−7.46 (m, 1H),

1.38 (s, 9H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 165.5, 155.4, 148.3,

138.8, 136.4, 134.8, 132.4, 128.0, 127.5, 127.2, 125.8, 121.8, 121.6, 116.5,

35.1, 31.3; FT-IR (neat, cm⁻¹) ν 3349, 1665, 1531, 1485. Anal. Calcd for

C₂₀H₂₀N₂O (304.35 g/mol): C, 78.92; H, 6.62; N, 9.20. Found: C,

78.88; H, 6.68; N, 9.22.

4-Methoxy-3-methyl-N-(quinolin-8-yl)benzamide (SM14). 8-Ami-

noquinoline (10.9 mmol, 1.6 g) and Et₃N (14.7 mmol, 2.0 mL) in

dichloromethane (20 mL), followed by 4-methoxy-3-methylbenzoyl

chloride (12 mmol, 2.2 g) in dichloromethane (15 mL). The mixture

was stirred for 16 h at room temperature. After recrystallization

(ethanol/water), tan crystalline compound (3.18 g, 99% yield) was

obtained: mp = 121−123 °C (hexanes); ¹H NMR (500 MHz, CDCl₃,

ppm) δ 10.64 (s, IH) 8.97 (dd, J = 7.4, 1.3 Hz, 1H), 8.83 (dd, J = 4.4, 1.5

Hz, 1H), 8.14 (dd, J = 8.3, 1.8 Hz, 1H), 7.95−7.86 (m, 2H), 7.60−7.47

(m, 2H), 7.46−7.42 (m, 1H), 6.92 (d, J = 8.5 Hz, 1H), 1.55 (s, 3H), 0.92

(s, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) 165.4, 160.8, 148.2, 138.8,

136.5, 134.9, 129.9, 128.1, 127.6, 127.1, 126.9, 126.7, 121.7, 121.4, 116.4,

109.5, 55.6, 16.5. Anal. Calcd for C₁₈H₁₆N₂O₂292.33 g/mol): C, 73.95;

H, 5.52; N, 9.58. Found: C, 74.00; H, 5.50; N, 9.53.

N-(Quinolin-8-yl)-3-(triﬂuoromethyl)benzamide (SM13). 8-Amino-

quinoline (13.1 mmol, 1.9 g) and Et₃N (15.8 mmol, 2.2 mL) in

dichloromethane (35 mL), followed by 3-(triﬂuoromethyl)benzoyl

chloride (23.4 mmol, 3.4 g) in dichloromethane (25 mL). The mixture

was stirred for 16 h at room temperature. After recrystallization

(ethanol/water), tan crystalline compound (4.9 g, 96% yield) was

obtained: R_f= 0.25 (toluene/ethyl acetate 50/1), mp = 86−87 °C

(hexanes); ¹H NMR (500 MHz, CDCl₃, ppm) 10.84 (s, 1H), 8.93 (dd, J

= 7.4, 1.4 Hz, 1H), 8.90 (dd, J = 4.3, 1.5 Hz, 1H), 8.37 (s, 1H), 8.33−8.28

(m, 2H), 7.87− 7.84 (m, 1H), 7.74−7.62 (m, 3H), 7.59−7.55 (m, IH);

¹³C NMR (100 MHz, CDCl₃, ppm) δ 164.0, 148.5, 138.7, 136.6, 136.0,

134.2, 131.5 (q, J_C−F= 32.0 Hz), 130.4, 129.5, 128.5 (q, J_C−F= 3.7 Hz),

128.1, 127.5, 124.7 (q, J_C−F= 3.7 Hz), 123.9 (q, J_C−F= 272.6 Hz), 122.3,

121.9, 116.9; ¹⁹F NMR (376 MHz, CDCl₃, ppm) δ −62.5 (s). Anal.

Calcd for C₁₇H₁₁F₃N₂O (316.28 g/mol): C, 64.56; H, 3.51; N, 8.86.

Found: C, 64.58; H, 3.45; N, 8.80.

4-Methoxy-N-(quinolin-8-yl)benzamide (SM15). 8-Aminoquino-

line (20.8 mmol, 3.0 g) and Et₃N (25 mmol, 3.50 mL), in

dichloromethane (35 mL), followed by 4-methoxybenzoyl chloride

(21.8 mmol, 3.7 g) in dichloromethane (20 mL). The mixture was

stirred for 24 h at room temperature. A crystalline compound (5.6 g,

98% yield) was obtained: mp = 117−118 °C (hexanes); ¹H NMR (500

MHz, CDCl₃, ppm) δ 10.67 (s, IH), 8.92 (dd, J = 7.3, 1.4 Hz, 1H), 8.84

(dd, J = 4.3, 1.5 Hz, 1H), 8.15 (dd, J = 8.3, 1.6 Hz, 1H), 8.08−8.03 (m,

N

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a

Table 8. Alkylation of Picolinamides: Optimization of Solvent

% GC yield

entry

solvent, 0.50 mL

A

B

1

2

3

4

5

6

7

CF₃CH₂OH

CF₃CH(OH)CF₃

CH₃COOH

Piv-OH

26

52

36

20

50

47

50

19

29

13

5

H₂O, m-xylene

H₂O

24

23

14

H₂O (0.15 mL)

a

Dodecane internal standard; amide (0.5 mmol), BuI (4 mmol).

a

Table 9. Alkylation of Picolinamides: Optimization of Additives

% GC yield

entry

additive

A

B

1

2

3

4

5

6

7

8

9

no additive

45

95

76

65

95

55

58

84

70

15

5

10% CuBr₂

20% CuBr₂

14

17

4

10% Cu(NO₃)₂

20% Cu(NO₃)₂

10% CuCl₂

20

19

10

17

10% CuCO₃

10% CuOAc

10% MnO₂

a

Dodecane internal standard; amide (0.5 mmol), BuI (4 mmol).

2H), 7.60−7.49 (m, 2H), 7.48−7.43 (m, 1H), 7.05−7.01 (m, 2H), 3.87

(s, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 165.0, 162.5, 148.3,

138.8, 136.4, 134.8, 129.2, 128.0, 127.6, 127.5, 121.7, 121.5, 116.4, 114.0,

55.5. Anal. Calcd for C₁₇H₁₄N₂O₂(278.31 g/mol): C, 73.37; H, 5.07; N,

10.07. Found: C, 73.35; H, 5.09; N, 9.95.

2-(2-Fluoro[1,1′-biphenyl]-4-yl)-N-(quinolin-8-yl)propanamide

(SM16). 8-Aminoquinoline (7.4 mmol, 1.1 g) and Et₃N (8.2 mmol, 1.2

mL) in dichloromethane (25 mL), followed by 2-(2-ﬂuorobiphenyl-4-

yl)propanoyl chloride (8.2 mmol, 2.1 g) in dichloromethane (20 mL).

The mixture was stirred for 16 h at room temperature. After

chromatography (toluene/ethyl acetate 25/1), tan crystalline com-

pound (2.6 g, 84% yield) was obtained: R_f= 0.40 (toluene/ethyl acetate

1

25/1); H NMR (500 MHz, CDCl₃, ppm) δ 9.98 (s, 1H), 8.81−8.69

(m, 2H), 8.11 (dd, J = 8.3, 0.9 Hz, 1H), 7.57−7.27 (m, 11H), 4.00−3.92

(m, 1H), 1.72 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm;

list of signals, C−F coupling not assigned) δ 172.1, 161.2, 158.7, 147.4,

142.6, 142.5, 138.5, 136.4, 135.6, 134.5, 131.3, 131.2, 129.1, 129.0, 128.6,

128.4, 128.1, 128.0, 127.8, 127.4, 123.8, 123.7, 121.8, 127.7, 116.5, 115.6,

115.4, 48.2, 18.7; ¹⁹F NMR (376 MHz, CDCl₃, ppm) δ −117.3 (m);

O

dx.doi.org/10.1021/jo4013628 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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a

Table 10. Alkylation of Picolinamides: Optimization of Base

% GC yield

entry

base

A

B

1

2

3

4

5

6

7

8

K₃PO₄

95

49

99

54

28

7

5

Na₃PO₄

K₂CO₃

Na₂CO₃

Cs₂CO₃

CsOAc

K₂HPO₄

NaOAc

20

0

20

10

14

10

18

32

6

a

Dodecane internal standard; amide (0.5 mmol), BuI (4 mmol).

HRMS electrospray (m/z) [M⁺+ Na] calcd for C₂₄H₁₉FN₂O

393.13792, found 393.13782, error = 1.16 ppm.

Optimization of the Additive Used for the Alkylation of N-(1-

Phenylethyl)picolinamide. A 2-dram screw-cap vial was charged with

Pd(OAc)₂(5 mol %, 6 mg), N-(1-phenylethyl)picolinamide (0.5 mmol,

134 mg), iodobutane (2 mmol, 367 mg), and K₃PO₄(2.0 mmol, 424

mg). The additive (10 mol %) was added to this mixture (Table 9). The

resulting suspension was stirred in an oil bath at 120 °C. After 24 h, the

reaction mixture was cooled and diluted with dichloromethane (4 mL)

followed by GC−MS analysis using dodecane as an internal standard as

described earlier.

Optimization of the Base Used for the Alkylation of N-(1-

Phenylethyl)picolinamide. A 2-dram screw-cap vial was charged with

Pd(OAc)₂(5 mol %, 6 mg), CuBr₂(10 mol %, 11 mg), N-(1-

phenylethyl)picolinamide (0.5 mmol, 134 mg), iodobutane (2 mmol,

367 mg), base (2 mmol), and water (0.30 mL). The resulting suspension

was stirred in oil bath at 120 °C. After 24 h, the reaction mixture was

cooled and diluted with dichloromethane (4 mL) followed by analysis

with GC−MS using dodecane as an internal standard as described

earlier.

Optimization of Reaction Conditions for Arylation of N-(2-

Phenylpropan-2-yl)picolinamide. A 2-dram screw-cap vial was charged

with Pd(OAc)₂(5 mol %, 11 mg), N-(2-phenylpropan-2-yl)-

picolinamide (1.0 mmol, 246 mg), and 1-iodo-4-methylbenzene (4.0

mmol, 896 mg). The reactants and solvent were added to this mixture

(Table 7). The resulting suspension was stirred in an oil bath at the

speciﬁed temperature. After the designated time, the reaction mixture

was cooled, diluted with dichloromethane (4 mL), and analyzed by

GC−MS.

Determination of the GC Conversion Using Internal Standard. The

GC conversion for the optimization experiments was calculated on the

basis of an internal standard (dodecane) as described here. First, a 1:1

molar mixture of dodecane and the pure target compound was dissolved

in ethyl acetate and injected into GC to determine detector response

ratio F = A_tc/A_do(A_tc: area of target compound peak, A_do: area of

dodecane peak). Second, the reaction is set up as usual on 1 mmol scale

with the addition of dodecane as internal standard (0.3 mmol). After the

completion of reaction, 1 drop of reaction mixture is diluted with

CH₂Cl₂and injected into GC to determine area of dodecane (A_dor) and

the target compound (A_tcr). The amount of target compound in reaction

mixture can be calculated by the following equation: n_tcr= 0.3A_tcr/

(A_dorF) (mmol). The conversion is derived based on the amount of

starting material added (n_sm): C = (n_tcr/n_sm) × 100%.

Attempted Synthesis of N-((2,2″-Dimethyl[1,1′:3′,1″-terphenyl]-

2′-yl)methyl)picolinamide. A 2-dram screw-cap vial was charged with

Pd(OAc)₂(5 mol %, 11 mg), CuBr₂(10 mol %, 22 mg), N-

benzylpicolinamide (1.0 mmol, 224 mg), 2-iodotoluene (4.0 mmol, 872

mg), CsOAc (4.0 mmol, 794 mg), and tert-amyl alcohol (1.0 mL). The

resulting suspension was stirred at 140 °C for 24 h. An aliquot of the

reaction mixture was diluted with ethyl acetate and passed though a

short silica plug. GC−MS analysis indicated that no product was formed.

Solvent Optimization for the Alkylation of N-(1-Phenylethyl)-

picolinamide. A 2-dram screw-cap vial was charged with Pd(OAc)₂(5

mol %, 6 mg), N-(1-phenylethyl)picolinamide (0.5 mmol, 134 mg),

iodobutane (2 mmol, 367 mg), and K₃PO₄(2 mmol, 424 mg). The

solvent (0.50 mL) was added to this mixture (Table 8). The resulting

suspension was stirred in an oil bath at 140 °C. After 24 h, the reaction

mixture was cooled and diluted with dichloromethane (4 mL) followed

by analysis with GC−MS using dodecane as an internal standard as

described earlier.

General Procedure for the Arylation of sp²C−H Bonds of

Picolinamides. A 2-dram screw-cap vial was charged with Pd(OAc)₂

(5 mol %, 11 mg), CuBr₂(10 mol %, 22 mg), picolinamide (1 mmol),

aryl iodide (4 mmol), CsOAc (4 mmol, 794 mg), and tert-amyl alcohol

(0.5 mL). The resulting suspension was stirred at 140 °C for 24 h. The

reaction mixture was then extracted with dichloromethane (3 × 4 mL).

The extracts were combined, ﬁltered through a pad of cotton,

concentrated, and then loaded onto a chromatography column with

hexanes/ethyl acetate mixture as an eluent and subjected to column

chromatography. After concentration of the fractions containing the

product, the residue was dried under reduced pressure.

General Procedure for the Arylation of N-(Naphthalen-1-yl)-

picolinamide Using Pd(OAc)₂Catalyst and AgOAc Base. A 2-dram

screw-cap via was charged with Pd(OAc)₂(2 mol %, 4.4 mg), AgOAc

(166 mg, 1 mmol), aryl iodide (2 mmol), and N-(naphthalen-1-

yl)picolinamide (0.5 mmol, 125 mg). The resulting solution was stirred

at 140 °C for 24 h. The reaction mixture was then diluted with

dichloromethane (2 mL), ﬁltered through pad of Celite, concentrated,

and loaded on a chromatography column with hexane/ethyl acetate

mixture as an eluent.

N-(2-(4,4″-Dimethyl-[1,1′:3′,1″-terphenyl]-2′-yl)propan-2-yl)-

picolinamide (Table 2, Entry 1). A 2-dram screw-cap vial was charged

with Pd(OAc)₂(5 mol %, 11 mg), CuBr₂(10 mol %, 22 mg), N-(2-

phenylpropan-2-yl)picolinamide (1 mmol, 246 mg), 1-iodo-4-methyl-

benzene (4 mmol, 896 mg), CsOAc (4 mmol, 794 mg), and tert-amyl

P

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The Journal of Organic Chemistry

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alcohol (1.0 mL). The resulting suspension was stirred at 140 °C for 24

h. After chromatography (hexane/ethyl acetate 70/30), tan powder

(425 mg, 99% yield) was obtained: R_f= 0.45 (hexanes/ethyl acetate 70/

30); mp = 164−165 °C (hexanes); ¹H NMR (400 MHz, CDCl₃, ppm) δ

8.21−8.20 (m, 1H), 7.99−7.97 (m, 1H), 7.76−7.72 (m, 1H), 7.58 (br s,

1H), 7.31−7.28 (m, 1H), 7.17−7.13 (m, 5H), 7.02 (d, J = 7.3 Hz, 2H),

6.90 (d, J = 7.3 Hz, 2H), 2.25 (s, 6H), 1.60 (s, 6H); ¹³C NMR (100

MHz, CDCl₃, ppm) δ 162.0, 150.7, 147.1, 143.4, 141.8, 141.7, 136.9,

135.7, 132.8, 128.7, 128.2, 125.4, 124.9, 121.5, 57.5, 33.4, 21.2; FT-IR

(neat, cm⁻¹) ν 3369, 1679, 1527, 1444, 1224, 1042. Anal. Calcd for

C₂₉H₂₈N₂O (420.55 g/mol): C, 82.82; H, 6.71; N, 6.66. Found: C,

82.47; H, 6.69; N, 6.55.

0.9 Hz, 1H), 7.81−7.73 (m, 1H), 7.59−7.55 (m, 2H), 7.50−7.47 (m,

2H), 7.36−7.34 (m, 3H), 7.31−7.28 (m, 1H), 7.21−7.17 (m, 1H), 1.06

(s, 9H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 161.7, 149.8, 149.7,

147.6, 139.6, 137.8, 137.1, 135.6, 133.1, 130.7, 128.9, 128.4, 126.3, 126.0,

125.9, 125.2, 124.8, 122.3, 121.9, 34.3, 31.3; signal for one carbon could

not be located; FT-IR (neat, cm⁻¹) ν 1690, 1521, 1495; HRMS (m/z)

[M⁺] calcd for C₂₆H₂₄N₂O, 380.1889, found 380.1885, error = −1.1

ppm.

N-(8-(4-Methoxyphenyl)naphthalen-1-yl)picolinamide (Table 2,

Entry 6). A 2-dram screw-cap vial was charged with Pd(OAc)₂(5 mol %,

11 mg), CuBr₂(10 mol %, 22 mg), N-(naphthalen-1-yl)picolinamide

(1.0 mmol, 247 mg), 1-iodo-4-methoxybenzene (4.0 mmol, 936 mg),

CsOAc (4.0 mmol, 794 mg), and tert-amyl alcohol (1.0 mL). The

resulting suspension was stirred at 140 °C for 24 h. After

chromatography (hexanes/ethyl acetate 50/50), a beige powder (260

mg, 73% yield) was obtained: R_f= 0.31 (hexane/ethyl acetate 50/50);

mp = 107−108 °C (hexanes); ¹H NMR (400 MHz, CDCl₃, ppm) δ 9.71

(s, 1H), 8.30−8.28 (dd, J = 7.8, 1.4 Hz, 1H), 8.20−8.19 (m, 1H), 8.11

(d, J = 7.8 Hz, 1H), 7.86 (dd, J = 8.2, 0.9 Hz, 1H), 7.86 (dd, J = 8.2, 0.9

Hz, 1H), 7.80−7.56 (m, 2H), 7.59−7.55 (m, 1H), 7.49−7.45 (m, 1H),

7.34−7.30 (m, 4H), 6.75−6.67 (m, 2H), 3.59 (s, 3H); ¹³C NMR (100

MHz, CDCl₃, ppm) δ 162.0, 158.9, 150.1, 147.5, 137.4, 137.0, 135.5,

135.1, 133.1, 130.7, 130.4, 128.6, 126.4, 126.0, 125.8, 125.0, 122.3, 122.0,

113.6, 55.0; signal for one carbon could not be located; FT-IR (neat,

cm⁻¹) ν 1683, 1494, 1515, 1433, 1243, 1176, 1036. Anal. Calcd for

C₂₃H₁₈N₂O₂(354.40 g/mol): C, 77.95; H, 5.12; N, 7.90. Found: C,

77.68; H, 5.09; N, 7.78.

N-([1,1′:3′,1″-Terphenyl]-2′-ylmethyl)picolinamide (Table 2, Entry

2). A 2-dram screw-cap vial was charged with Pd(OAc)₂(5 mol %, 11

mg), CuBr₂(10 mol %, 22 mg), N-benzylpicolinamide (1 mmol, 212

mg), iodobenzene (4 mmol, 816 mg), CsOAc (4 mmol, 794 mg), and

tert-amyl alcohol (1.0 mL). The resulting suspension was stirred at 140

°C for 24 h. After chromatography (hexane/ethyl acetate 70/30), white

needles (360 mg, 99% yield) were obtained: R_f= 0.34 (hexanes/ethyl

1

acetate 70/30); mp = 119−120 °C (hexanes); H NMR (400 MHz,

CDCl₃, ppm) δ 8.44−8.43 (m, 1H), 7.98−7.96 (m, 1H), 7.78−7.72 (m,

2H), 7.43−7.29 (m, 14H), 4.49 (d, J = 5.1 Hz, 2H); ¹³C NMR (100

MHz, CDCl₃, ppm) δ 162.9, 149.8, 147.9, 143.9, 141.2, 137.1, 132.7,

129.8, 129.1, 128.3, 127.5, 127.4, 125.9, 122.0, 39.4; FT-IR (neat, cm⁻¹)

ν 3378, 1678, 1510, 1464, 1435, 1000. Anal. Calcd for C₂₅H₂₀N₂O

(364.44 g/mol): C, 82.39; H, 5.53; N, 7.69. Found: C, 82.50; H, 5.45; N,

7.68. When bromobenzene (4 mmol, 628 mg) was used instead of

iodobenzene, product was not detected by GC−MS.

N-(8-(4-Methoxyphenyl)naphthalen-1-yl)picolinamide (Table 2,

Entry 6). N-(Naphthalen-1-yl)picolinamide (127 mg, 0.5 mmol), 4-

iodoanisole (468 mg, 2 mmol), AgOAc (166 mg, 1.0 mmol), and

Pd(OAc)₂(4.4 mg, 0.01 mmol). The resulting suspension was stirred at

140 °C for 24 h. After column chromatography (hexanes/ethyl acetate

70/30), the solvent was evaporated to give white powder (176 mg, 98%

Ethyl 3′-Methoxy-2′-(picolinamidomethyl)[1,1′-biphenyl]-4-car-

boxylate (Table 2, Entry 3). A 2-dram screw-cap vial was charged

with Pd(OAc)₂(5 mol %, 11 mg), CuBr₂(10 mol %, 22 mg), N-(2-

methoxybenzyl)picolinamide (1 mmol, 247 mg), ethyl-4-iodobenzoate

(4 mmol, 1104 mg), CsOAc (4 mmol, 794 mg), and tert-amyl alcohol

(1.0 mL). The resulting suspension was stirred at 140 °C for 24 h. After

chromatography (hexane/ethyl acetate 60/40), white needles (353 mg,

92% yield) were obtained: R_f= 0.33 (hexanes/ethyl acetate 60/40); mp

= 163−164 °C (hexanes); ¹H NMR (400 MHz, CDCl₃, ppm) δ 8.50−

8.48 (m, 1H), 8.33−8.36 (m, 1H), 8.16−8.13 (m, 1H), 8.10−8.07 (m,

2H), 7.81−7.76 (m, 1H), 7.43−7.41 (m, 2H), 7.38−7.31 (m, 2H), 6.96

(d, J = 7.8 Hz, 1H), 6.89 (dd, J = 7.8, 0.9 Hz, 1H), 4.58 (d, J = 5.5 Hz,

2H), 4.37 (q, J = 7.3 Hz, 2H), 3.94 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H); ¹³C

NMR (100 MHz, CDCl₃, ppm) δ 166.6, 163.4, 158.8, 150.3, 148.1,

145.3, 143.0, 137.3, 129.6, 129.5, 128.7, 126.0, 123.6. 122.5, 122.3, 110.2,

61.0, 56.0, 38.6, 14.5; FT-IR (neat, cm⁻¹) ν 3396, 1709, 1668, 1584.

1512, 1462, 1271, 1176, 1023. Anal. Calcd for C₂₃H₂₂N₂O₄(390.43 g/

mol): C, 70.75; H, 5.68; N, 7.17. Found: C, 70.86; H, 5.65; N, 7.16.

N-(8-p-Tolylnaphthalen-1-yl)picolinamide (Table 2, Entry 4). N-

(Naphthalen-1-yl)picolinamide (5.1 g, 20.5 mmol), 4-iodotoluene (17.5

g, 80.3 mmol), AgOAc (5.1 g, 30.5 mmol), and Pd(OAc)₂(101 mg, 0.45

mmol). The resulting suspension was stirred at 140 °C for 24 h. After

column chromatography (hexanes/ethyl acetate 90/10 then hexanes/

ethyl acetate 65/35), the solvent was evaporated to give light brown

crystals (6.45 g, 91% yield): R_f= 0.50 (hexanes/ethyl acetate 65/35); mp

= 123−124 °C (hexanes); ¹H NMR (400 MHz, CDCl₃, ppm) δ 9.61 (s,

1H), 8.23 (dd, J = 7.7, 1.5 Hz, 1H), 8.18−8.16 (m, 1H), 8.10−8.08 (m,

1H), 7.86 (dd, J = 8.4, 1.5 Hz, 1H), 7.80−7.74 (m, 2H), 7.58−7.54 (m,

1H), 7.48−7.44 (m, 1H), 7.32−7.24 (m, 4H), 6.96 (d, J = 7.7 Hz, 2H),

2.80 (s, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 162.0, 150.0, 147.4,

139.9, 137.8, 137.0, 136.6, 135.6, 133.0, 130.5, 129.2, 128.9, 128.6, 126.5,

126.0, 125.7, 125.1, 125.0, 122.6, 121.9, 21.2; FT-IR (neat, cm⁻¹) ν

1689, 1493, 1433. Anal. Calcd for C₂₃H₁₈N₂O (388.4 g/mol): C, 81.63;

H, 5.36; N, 8.28. Found: C, 81.54; H, 5.35; N, 8.23.

1

yield): H NMR (400 MHz, CDCl₃, ppm) δ 9.71 (s, 1H), 8.30−8.28

(dd, J = 7.8, 1.4 Hz, 1H), 8.20−8.19 (d, J = 5.0, 1H), 8.11 (d, J = 7.8, 1H),

7.86 (dd, J = 8.2, 0.9 Hz, 1H), 7.86 (dd, J = 8.2, 0.9 Hz, 1H), 7.80−7.56

(m, 2H), 7.59−7.55 (m, 1H), 7.49−7.45 (m, 1H), 7.34−7.30 (m, 4H),

6.75−6.67 (m, 2H), 3.59 (s, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ

162.0, 158.9, 150.1, 147.5, 137.4, 137.0, 135.5, 135.1, 133.1, 130.7, 130.4,

128.6, 126.4, 126.0, 125.8, 125.0, 122.3, 122.0, 113.6, 55.0; signal for one

carbon could not be located. Anal. Calcd for C₂₃H₁₈N₂O₂(354.4 g/

mol): C, 77.95; H, 5.12; N, 7.90. Found: C, 77.68; H, 5.09; N, 7.78.

N-(8-(3-Methoxyphenyl)naphthalen-1-yl)picolinamide (Table 2,

Entry 7). N-(Naphthalen-1-yl)picolinamide (125 mg, 0.5 mmol), 3-

iodoanisole (468 mg, 2 mmol), AgOAc (166 mg, 1.0 mmol), and

Pd(OAc)₂(4.4 mg, 0.01 mmol). After column chromatography

(hexanes/ethyl acetate 70/30), the solvent was evaporated to give

white powder (178 mg, 99% yield): R_f= 0.30 (hexanes/ethyl acetate 70/

30); mp = 99−100 °C (hexanes); ¹H NMR (400 MHz, CDCl₃, ppm) δ

9.60 (s, 1H), 8.23−8.18 (m, 2H), 8.10−8.08 (m, 1H), 7.88 (dd, J = 8.2,

1.4 Hz, 1H), 7.82−7.75 (m, 2H), 7.60−7.56 (m, 1H), 7.47 (dd, J = 8.2,

7.3 Hz, 1H), 7.34−7.31 (m, 2H), 7.07−7.04 (m, 2H), 6.91−6.93 (m,

2H), 6.52−6.49 (m, 1H), 3.67 (s, 3H); ¹³C NMR (100 MHz, CDCl₃,

ppm) δ 162.2, 159.4, 149.9, 147.5, 144.2, 137.6, 137.1, 135.5, 132.9,

130.3, 129.2, 128.9, 126.6, 126.0, 125.9, 125.3, 125.0, 123.1, 121.9, 121.7,

114.0, 113.3, 55.2; FT-IR (neat, cm⁻¹) ν 1682, 1521, 1577, 1498, 1427,

1215, 1160, 1041. Anal. Calcd for C₂₃H₁₈N₂O₂(354.4 g/mol): C, 77.95;

H, 5.12; N, 7.90. Found: C, 77.69; H, 5.10; N, 7.83.

Ethyl 4-(8-(Picolinamido)naphthalen-1-yl)benzoate (Table 2,

Entry 8). N-(Naphthalen-1-yl)picolinamide (122 mg, 0.5 mmol), ethyl

4-iodobenzoate (122 mg, 2 mmol), AgOAc (166 mg, 1.0 mmol), and

Pd(OAc)₂(4.4 mg, 0.01 mmol). After column chromatography

(hexanes/ethyl acetate 70/30), the solvent was evaporated to give

white powder (179 mg, 92% yield): R_f= 0.28 (hexanes/ethyl acetate 70/

30); mp = 82−83 °C (hexanes); ¹H NMR (400 MHz, CDCl₃, ppm) δ

9.35 (s, 1H), 8.12−8.10 (m, 2H), 8.06 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 8.3

Hz, 1H), 7.83−7.80 (m, 3H), 7.76−7.70 (m, 1H), 7.60−7.56 (m, 1H),

7.50−7.46 (m, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 7.4 Hz, 1H),

7.24−7.22 (m, 1H), 4.29 (q, J = 7.3 Hz, 2H), 1.32 (t, J = 7.3 Hz, 3H). ¹³C

NMR (100 MHz, CDCl₃, ppm) δ 166.3, 162.0, 149.6, 147.7, 147.5,

N-(8-(4-tert-Butylphenyl)naphthalen-1-yl)picolinamide (Table 2,

Entry 5). N-(Naphthalen-1-yl)picolinamide (124 mg, 0.5 mmol), 4-tert-

butyliodobenzene (520 mg, 2 mmol), AgOAc (166 mg, 1.0 mmol), and

Pd(OAc)₂(4.4 mg, 0.01 mmol). After column chromatography

(hexanes/ethyl acetate 80/20), the solvent was evaporated to give

white powder (190 mg, 99% yield): R_f= 0.34 (hexanes/ethyl acetate 80/

20); mp = 136−137 °C (hexanes); ¹H NMR (400 MHz, CDCl₃, ppm) δ

9.60 (s, 1H), 8.32−8.18 (m, 2H), 8.11−8.10 (m, 1H), 7.88 (dd, J = 8.2,

Q

dx.doi.org/10.1021/jo4013628 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

137.1, 136.8, 135.5, 132.5, 130.2, 129.4, 129.2, 128.8, 126.9, 126.2, 125.9,

125.4, 125.0, 123.8, 122.0, 60.8, 14.5; signal for one carbon could not be

located; FT-IR (neat, cm⁻¹) ν 1710, 1682, 1495, 1266, 1102. Anal. Calcd

for C₂₅H₂₀N₂O₃(396.4 g/mol): C, 75.74; H, 5.08; N, 7.07. Found: C,

75.63; H, 5.05; N, 7.00.

2H), 7.93 (dd, J = 8.2, 2.3 Hz, 1H), 7.84 (dd, J = 8.2, 1.3 Hz, 1H), 7.79−

7.75 (m, 1H), 7.62−7.58 (m, 1H), 7.52−7.48 (m, 3H), 7.39 (d, J = 7.8

Hz, 2H), 7.34−7.30 (m, 2H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ

162.0, 149.3, 147.6, 146.7, 137.3, 136.3, 135.6, 132.4, 130.5, 129.5, 128.4,

128.9 (q, J_C−F= 32.6 Hz), 127.0, 126.3, 125.6, 125.4, 125.4, (q, J_C−F= 5.8

Hz), 125.1, 124.9 (q, J_C−F= 3.8), 124.1 (J_C−F= 270.8), 121.9; FT-IR

(neat, cm⁻¹) ν 1670, 1491, 1320, 1185, 1141, 1111, 1070, 1058, 1018.

Anal. Calcd for C₂₃H₁₅F₃N₂O (392.4 g/mol): C, 70.40; H, 3.85; N, 7.14.

Found: C, 70.59; H, 3.65; N, 7.14.

Large-Scale Synthesis of N-(1,2′-Binaphthyl-8-yl)picolinamide

(Table 2, Entry 12). N-(Naphthalen-1-yl)picolinamide (8.68 g, 35

mmol), 2-iodonaphthalene (26.7 g, 105 mmol), AgOAc (8.71 g, 52.5

mmol), and Pd(OAc)₂(392 mg, 1.75 mmol). The ﬂask was sealed with

rubber septum and then heated with stirring at 140 °C for 24 h. After the

reaction was complete, the mixture was cooled and ethyl acetate (150

mL) was added. The mixture was ﬁltered, and the ﬁltrate was washed

with brine (150 mL). The layers were separated and the aqueous

solution was extracted with ethyl acetate (2 × 50 mL). The organic

layers were combined, dried with MgSO₄, and concentrated. The

residue was subjected to column chromatography (dichloromethane/

ethyl acetate 50/50), and the solvent was evaporated and the residue

obtained was recrystallized from methanol to give light brown crystals

(8.5 g, 65% yield): R_f= 0.32 (dichloromethane/ethyl acetate 50/50);

mp = 155−156 °C (hexanes); ¹H NMR (400 MHz, CDCl₃, ppm) δ 9.56

(s, 1H), 8.31 (dd, J = 7.8, 1.4 Hz, 1H), 8.03 (s, 1H), 7.94−7.87 (m, 3H),

7.81 (dd, J = 8.3, 0.9 Hz, 1 H), 7.61−7.47 (m, 6H), 7.41−7.34 (m, 3H);

¹³C NMR (100 MHz, CDCl₃, ppm) δ 162.1, 149.4, 146.8, 140.7, 137.6,

N-(8-(3-Chlorophenyl)naphthalen-1-yl)picolinamide (Table 2,

Entry 9). N-(Naphthalen-1-yl)picolinamide (135 mg, 0.5 mmol), 1-

chloro-3-iodobenzene (476 mg, 2 mmol), AgOAc (166 mg, 1.0 mmol),

and Pd(OAc)₂(4.4 mg, 0.01 mmol). After column chromatography

(hexanes/ethyl acetate 80/20), the solvent was evaporated to give white

powder (190 mg, 98% yield): R_f= 0.30 (hexanes/ethyl acetate 80/20);

mp = 120−121 °C (hexanes); ¹H NMR (400 MHz, CDCl₃, ppm) δ 9.50

(s, 1H), 8.30 (d, J = 4.6 Hz, 1H), 8.18 (dd, J = 7.8, 0.9 Hz, 1H), 8.10 (d, J

= 7.8 Hz, 1H), 7.89 (dd, J = 8.2, 1.4 Hz, 1H), 7.82−7.76 (m, 2H), 7.60−

7.56 (m, 1H), 7.49−7.47 (m, 2H), 7.37−7.34 (m, 1H), 7.28 (dd, J = 7.4,

1.4 Hz, 1H), 7.18−7.15 (m, 1H), 7.01−6.96 (m, 1H), 6.92−6.90 (m,

1H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 161.9, 149.6, 147.5, 144.7,

137.2, 136.2, 135.5, 134.2, 132.6, 130.4, 129.3, 129.1, 129.0, 127.8, 126.8,

126.2, 126.1, 125.2, 125.0, 123.3, 122.0; signal for one carbon could not

be located; FT-IR (neat, cm⁻¹) ν 1684, 1526, 1498, 1432. Anal. Calcd for

C₂₂H₁₅ClN₂O (358.8 g/mol): C, 73.64; H, 4.21; N, 7.81. Found: C,

73.89; H, 4.09; N, 7.76.

N-(8-(4-Bromophenyl)naphthalen-1-yl)picolinamide (Table 2,

Entry 10). A 2-dram screw-cap vial was charged with Pd(OAc)₂(5

mol %, 11 mg), CuBr₂(10 mol %, 22 mg), N-(naphthalen-1-

yl)picolinamide (1.0 mmol, 251 mg), 1-bromo-4-iodobenzene (4.0

mmol, 1.13 g), CsOAc (4.0 mmol, 794 mg), and tert-amyl alcohol (1.0

mL). The resulting suspension was stirred at 140 °C for 24 h. After

chromatography (hexane/ethyl acetate 80/20), light brown powder

(342 mg, 84% yield) was obtained: R_f= 0.33 (hexanes/ethyl acetate 80/

20); mp = 134−135 °C (hexanes); ¹H NMR (400 MHz, CDCl₃, ppm) δ

9.56 (s, 1H), 8.32−8.30 (m, 1H), 8.21−8.20 (m, 1H), 8.12 (d, J = 7.8

Hz, 1H), 7.91 (dd, J = 8.3, 0.9 Hz, 1H), 7.84−7.80 (m, 2H), 7.61−7.57

(m, 1H), 7.50−7.46 (m, 1H), 7.42−7.39 (m, 1H), 7.32−7.28 (m, 5H);

¹³C NMR (100 MHz, CDCl₃, ppm) δ 162.0, 149.5, 147.9, 141.9, 137.2,

136.6, 135.5, 133.8, 133.1, 132.7, 130.7, 129.0, 128.1, 128.0, 127.7, 127.6,

127.4, 126.4, 126.3, 126.1, 125.8, 125.7, 125.1, 125.0, 122.3, 121.5; FT-

IR (neat, cm⁻¹) ν 1692, 1496. Anal. Calcd for C₂₆H₁₈N₂O (374.4 g/

mol): C, 83.40; H, 4.85; N, 7.48. Found: C, 83.19; H, 4.88; N, 7.39.

Ethyl 4′,5′-Dimethoxy-2′-(2-(picolinamido)ethyl)[1,1′-biphenyl]-

4-carboxylate (Table 2, Entry 13). A 2-dram screw-cap vial was

charged with Pd(OAc)₂(5 mol %, 11 mg), CuBr₂(10 mol %, 22 mg), N-

(3,4-dimethoxyphenethyl)picolinamide (1.0 mmol, 265 mg), ethyl 4-

iodobenzoate (4.0 mmol, 1.10 g), CsOAc (4.0 mmol, 794 mg), and tert-

amyl alcohol (1.0 mL). The resulting suspension was stirred at 140 °C

for 24 h. After chromatography (hexane/ethyl acetate 40/60), white

powder (207 mg, 52% yield) was obtained: R_f= 0.39 (hexanes/ethyl

136.4, 135.6, 132.6, 131.3, 130.9, 130.5, 129.2, 129.7, 126.3, 126.2, 125.0,

123.2, 122.0, 121.4; signal for one carbon could not be located; FT-IR

(neat, cm⁻¹) ν 1687, 1498, 1433, 1009. Anal. Calcd for C₂₂H₁₅BrN₂O

(403.3 g/mol): C, 65.52; H, 3.75; N, 6.95. Found: C, 65.10; H, 3.54; N,

6.82.

1

acetate 40/60); mp = 133−134 °C (hexanes); H NMR (400 MHz,

CDCl₃, ppm) δ 8.50−8.49 (m, 1H), 8.14−8.11 (m, 1H), 8.06−8.03 (m,

2H), 7.97−7.95 (m, 1H), 7.84−7.80 (m, 1H), 7.42−7.37 (m, 3H), 6.86

(s, 1H), 6.72 (s, 1H), 4.34 (q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 3.86 (s, 3H),

3.52 (q, J = 7.3 Hz, 2H), 2.85 (t, J = 7.3 Hz, 2H), 1.41 (t, J = 7.3 Hz, 2H);

¹³C NMR (100 MHz, CDCl₃, ppm) δ 166.6, 164.2, 149.9, 148.7, 148.0,

147.4, 146.2, 137.5, 133.6, 129.6, 129.1, 128.5, 126.3, 122.3, 113.1, 112.7,

61,1, 56.1, 56.0, 40.6, 32.6, 14.5; signal for one carbon could not be

located; FT-IR (neat, cm⁻¹) ν 3364, 1706, 1666, 1520, 1502, 1440, 1272,

1237, 1212, 1139, 1097, 1032. Anal. Calcd for C₂₅H₂₆N₂O₅(434.48 g/

mol): C, 69.11; H, 6.03; N, 6.45. Found: C, 69.08; H, 5.95; N, 6.44.

N-(2,6-Di((E)-styryl)benzyl)picolinamide (Table 2, Entry 14). A 2-

dram screw-cap vial was charged with Pd(OAc)₂(5 mol %, 11 mg),

CuBr₂(10 mol %, 22 mg), N-benzylpicolinamide (1 mmol, 194 mg),

(E)-(2-iodovinyl)benzene (4 mmol, 0.92 g), CsOAc (4 mmol, 794 mg),

and tert-amyl alcohol (0.5 mL). The resulting suspension was stirred at

140 °C for 24 h. After chromatography (hexanes/ethyl acetate 70/30),

tan needles (269 mg, 86% yield) were obtained: R_f= 0.35 (hexanes/

N-(8-(4-Bromophenyl)naphthalen-1-yl)picolinamide (Table 2,

Entry 10). N-(Naphthalen-1-yl)picolinamide (121 mg, 0.5 mmol), 1-

bromo-4-iodobenzene (564 mg, 2 mmol), AgOAc (166 mg, 1.0 mmol),

and Pd(OAc)₂(4.4 mg, 0.01 mmol). The resulting suspension was

stirred at 140 °C for 24 h. After column chromatography (hexanes/ethyl

acetate 70/30), the solvent was evaporated to give white powder (161

1

mg, 82% yield): H NMR (400 MHz, CDCl₃, ppm) δ 9.56 (s, 1H),

8.32−8.30 (m, 1H), 8.21−8.20 (m, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.91

(dd, J = 8.3, 0.9 Hz, 1H), 7.84−7.80 (m, 2H), 7.61−7.57 (m, 1H), 7.50−

7.46 (m, 1H), 7.42−7.39 (m, 1H), 7.32−7.28 (m, 5H); ¹³C NMR (100

MHz, CDCl₃, ppm) δ 162.0, 149.5, 147.9, 141.9, 137.2, 136.4, 135.6,

132.6, 131.3, 130.9, 130.5, 129.2, 129.7, 126.3, 126.2, 125.0, 123.2, 122.0,

121.4. Signal for one carbon could not be located. Anal. Calcd for

C₂₂H₁₅BrN₂O (403.3 g/mol): C, 65.52; H, 3.75; N, 6.95. Found: C,

65.10; H, 3.54; N, 6.82.

Large-Scale Synthesis of N-(8-(4-(Triﬂuoromethyl)phenyl)-

naphthalen-1-yl)picolinamide (Table 2, Entry 11). N-(Naphthalen-

1-yl)picolinamide (12.4 g, 50 mmol), 4-iodobenzotriﬂuoride (27.2 g,

100 mmol), AgOAc (12.45 g, 75 mmol), and Pd(OAc)₂(224 mg, 1.0

mmol). The ﬂask was sealed with rubber septum and then heated with

stirring at 140 °C for 24 h. After the reaction was complete, the mixture

was cooled and 150 mL of ethyl acetate was added. The mixture was

ﬁltered and the ﬁltrate was washed with brine (150 mL). The layers were

separated and the aqueous solution was extracted with ethyl acetate (2 ×

50 mL). The organic layers were combined, dried with MgSO₄, and

concentrated. The residue was subjected to column chromatography

(hexanes/ethyl acetate 65/35), and the solvent was evaporated to give

light orange crystals (16.3 g, 84% yield): R_f= 0.48 (hexanes/ethyl

1

ethyl acetate 70/30); mp = 145−146 °C (hexanes); H NMR (400

MHz, CDCl₃, ppm) δ 8.43−8.41 (m, 1H), 8.23−8.21 (m, 1H), 8.14−

8.12 (m, 1H), 7.82−7.78 (m, 1H), 7.61−7.53 (m, 8H), 7.40−7.34 (m,

6H), 7.27−7.24 (m, 2H), 7.02 (d, J = 16.0 Hz, 2H), 4.98 (d, J = 5.5 Hz,

2H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 163.9, 149.8, 148.1, 138.3,

137.4, 137.3, 132.5, 132.4, 128.7, 128.5, 127.9, 126.9, 126.2, 126.0, 125.9,

122.4, 37.4; FT-IR (neat, cm⁻¹) ν 3395, 1677, 1515. Anal. Calcd for

C₂₉H₂₄N₂O (416.51g/mol): C, 83.63; H, 5.81; N, 6.73. Found: C,

83.89; H, 5.70; N, 6.57.

General Procedure for the Hydrolysis of the Arylated Picolina-

mides. The N-(8-arylnaphthalen-1-yl)picolinamide was dissolved in

ethanolic NaOH solution (NaOH in EtOH/H₂O 10/1) and reﬂuxed for

6 h. The reaction mixture was cooled and diluted with an equal volume

1

acetate 70/30); mp = 155−156 °C (hexanes); H NMR (400 MHz,

CDCl₃, ppm) δ 9.34 (s, 1H), 8.15 (d, J = 4.1 Hz, 1H), 8.09−8.07 (m,

R

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of water. The product was extracted with dichloromethane (3 × 60 mL).

The combined organic layers were combined, dried with MgSO₄, and

concentrated. The crude compound was subjected to column

chromatography, the fractions containing the product were combined,

and the solvent was evaporated to give pure 8-arylnaphthalen-1-amines.

8-p-Tolylnaphthalen-1-amine (6). N-(8-p-tolylnaphthalen-1-yl)-

picolinamide (10.1 g, 30 mmol), ethanolic NaOH solution (12 g

NaOH, 300 mmol in EtOH/H₂O 10/1 v/v, 120 mL). After

chromatography (hexane/ethyl acetate/triethylamine 94/5/1), beige

crystals were obtained (7.0 g, quantitative yield): R_f= 0.16 (hexane/

dichloromethane (35 mL). The resulting mixture was cooled in ice bath.

Propionyl chloride (1.55 mL, 17.4 mmol) in dichloromethane (10 mL)

was added dropwise. The reaction mixture was warmed to room

temperature and stirred for 24 h. The reaction mixture was diluted with

water (25 mL) and the layers were separated. The organic layer was

dried with MgSO₄, concentrated and subjected to column chromatog-

raphy (hexane/ethyl acetate 75/25) to give 2.50 g (99% yield) of a white

powder: R_f₁= 0.29 (hexane/ethyl acetate 75/25); mp = 134−135 °C

(hexanes); H NMR (400 MHz, CDCl₃, ppm) δ 8.14 (d, J = 7.1 Hz,

1H), 7.85 (dd, J = 8.2, 1.4 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.50−7.42

(m, 2H), 7.33−7.28 (m, 4H), 7.26−7.25 (m, 1H), 7.15 (s, 1H), 2.45 (s,

3H), 1.57 (q, J = 7.3 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃, ppm) δ 171.5, 140.6, 137.7, 136.8, 135.2, 133.3, 129.9,

129.4, 129.0, 126.1, 125.7, 124.7, 124.0, 121.2, 30.5, 21.3, 9.4; signal for

one carbon could not be located; FT-IR (neat, cm⁻¹) ν 1651, 1378,

1219; HRMS electrospray (m/z) [M⁺+ Na] calcd for C₂₀H₁₉NO,

312.13644, found 312.13589, error = 0.87 ppm.

Arylation of Naphthyl Propanamide: Ethyl 4-(1-Propionamido-8-

p-tolylnaphthalen-2-yl)benzoate (10). A 2-dram screw-cap vial was

charged with Pd(OAc)₂(5 mol %, 6 mg), AgOAc (166 mg, 1 mmol),

ethyl 4-iodobenzoate (0.52 g, 2 mmol), N-(8-p-tolylnaphthalen-1-

yl)propionamide (149.9 mg, 0.5 mmol), and triﬂuoroacetic acid (0.5

mL). The resulting solution was stirred at 110 °C for 3 h. The reaction

mixture was diluted with dichloromethane (2 mL), ﬁltered through a

pad of Celite, and concentrated. Puriﬁcation by chromatography

(hexanes/ethyl acetate 80/20) gave white powder (180 mg, 80% yield):

R_f= 0.09 (hexanes/ethyl acetate 80/20); mp = 259−260 °C (hexanes);

¹H NMR (400 MHz, CDCl₃, ppm) δ 8.00 (d, J = 8.2 Hz, 2H), 7.94−7.89

1

ethyl acetate/triethylamine 94/5/1); mp = 73−74 °C (hexanes); H

NMR (400 MHz, CDCl₃, ppm) δ 7.75 (d, J = 8.1 Hz, 1H), 7.38−7.22

(m, 7H), 7.13 (d, J = 7.0 Hz, 1H), 6.60 (d, J = 7.3 Hz, 1H), 3.74 (s, 2H),

2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 143.8, 140.6, 138.4,

137.3, 135.9, 129.2, 128.8, 128.6, 128.4, 126.6, 124.7, 121.0, 119.1, 111.4,

21.4; FT-IR (neat, cm⁻¹) ν 3490, 3393. 1615, 1579, 1522. Anal. Calcd

for C₁₇H₁₅N 233.3 g/mol): C, 87.52; H, 6.48; N, 6.00. Found: C, 87.44;

H, 6.42; N, 5.96.

8-(4-(Triﬂuoromethyl)phenyl)naphthalen-1-amine (7). N-(8-(4-

(Triﬂuoromethyl)phenyl)naphthalen-1-yl)picolinamide (16.3 g, 42

mmol), NaOH (16.8 g, 420 mmol) in EtOH/H₂O (10/1 v/v, 200

mL). After chromatography (hexane/ethyl acetate/triethylamine 94/5/

1), beige crystals were obtained (9.0 g, 75%): R_f= 0.21 (hexane/ethyl

acetate/triethylamine 94/5/1); mp = 108−109 °C (hexanes); ¹H NMR

(400 MHz, CDCl₃, ppm) δ 7.80 (dd, J = 8.2, 0.9 Hz, 1H), 7.68 (d, J = 7.8

Hz, 2H), 7.56 (d, J = 7.8 Hz, 2 H), 7.41−7.28 (m, 3H), 7.12 (dd, J = 8.7,

1.4, 1H), 6.64 (dd, J = 8.7, 1.4 Hz, 1H), 3.56 (s, 2 H).¹³C NMR (100

MHz, CDCl₃, ppm) δ 147.3, 143.4, 136.9, 135.9, 129.8, 129.7 (q, J_C−F

=

23.0 Hz), 129.5, 128.5, 126.9, 125.0 (q, J_C−F= 3.8 Hz), 124.6, 124.3

(J_C−F= 272.2), 120.4, 119.4, 111.8; FT-IR (neat, cm⁻¹) ν 3707, 3618,

2973, 2922, 2865, 2844, 1323, 1057, 1032, 1015. Anal. Calcd for

C₁₇H₁₂F₃N (287.3 g/mol): C, 71.07; H, 4.21; N, 4.88. Found: C, 71.23;

H, 4.12; N, 4.82.

(m, 2H), 7.50−7.45 (m, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.30 (dd, J = 7.2,

0.7 Hz, 1H), 7.26−7.21 (m, 4H), 6.38 (s, 1H), 4.36 (q, J = 7.3 Hz, 2H),

2.40 (s, 3H), 1.39 (t, J = 7.3 Hz, 3H), 1.22 (q, J = 7.4 Hz, 2H), 0.57 (t, J =

7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 171.6, 166.6, 145.7,

142.0, 138.6, 138.4, 136.6, 135.1, 131.0, 129.4, 129.3, 129.1, 129.0, 128.9,

128.8, 128.7, 128.6, 128.4, 127.9, 125.4, 61.0, 29.1, 21.2, 14.5, 9.0; FT-IR

(neat, cm⁻¹) ν 3710, 3680, 2956, 2844, 1716, 1662, 1266, 1055, 1033,

1014; HRMS electrospray (m/z) [M⁺+ Na] calcd for C₂₉H₂₇NO₃Na

460.18831, found 460.18870, error = 0.84 ppm.

1,2′-Binaphthyl-8-amine (8). N-(1,2′-Binaphthyl-8-yl)picolinamide

(8.23 g, 22 mmol), NaOH (8.8 g, 220 mmol) in EtOH/H₂O (10/1 v/v,

100 mL). After chromatography (hexane/dichloromethane 50/50),

light brown crystals were obtained (5.2 g, 88% yield): R_f= 0.26 (hexane/

dichloromethane 50/50); mp = 113−114 °C (hexanes); ¹H NMR (400

MHz, CDCl₃, ppm) δ 7.91−7.84 (m, 4H), 7.81−7.79 (m, 1H), 7.57−

7.51 (m, 3H), 7.41−7.26 (m, 3H), 7.22−7.20 (m, 1H), 6.60 (dd, J = 7.3,

1.4 Hz, 1H), 3.71 (s, 2H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 143.9,

141.3, 138.3, 136.0, 132.9, 132.6, 128.9, 128.7, 128.2, 128.0, 127.9, 127.6,

127.5, 126.8, 126.7, 126.4, 124.7, 120.9, 119.1, 111.3; FT-IR (neat,

cm⁻¹) ν 3707, 3681, 2972, 2922, 2865, 2844, 1055, 1032, 1014. Anal.

Calcd for C₂₀H₁₅N (269.2 g/mol): C, 89.19; H, 5.61; N, 5.20. Found: C,

8.39; H, 5.56; N, 5.18.

Cleavage of the Picolinic Acid Auxiliary: [1,1′:3′,1″-Terphenyl]-2′-

ylmethanamine (5). A known procedure was followed.⁹N-([1,1′:3′,1″-

Terphenyl]-2′-ylmethyl)picolinamide 4 (0.5 mmol, 182 mg) (0.5 mmol,

67 mg), n-butylamine (5 mmol, 0.5 mL), and toluene (1.5 mL) were

mixed in a 2-dram vial inside glovebox. The mixture was shaken until the

contents dissolved. Anhydrous AlCl₃(0.5 mmol, 67 mg) was then added

to the mixture. The vial was capped, taken outside the glovebox, heated,

and stirred at 90 °C for 24 h. After the reaction was complete, water (2

mL) was added to the reaction mixture. The mixture was extracted with

ethyl acetate (3 × 5 mL). The organic layers were combined,

concentrated, and puriﬁed by column chromatography in hexanes/

ethyl acetate 60/40. The fractions containing the product were

combined, concentrated and the solvent was evaporated to give white

crystals (118 mg, 91% yield): R_f= 0.12 (hexanes/ethyl acetate 60/40);

mp = 70−72 °C (hexanes); ¹H NMR (400 MHz, CDCl₃, ppm) δ 7.44−

7.30 (m, 12 H), 7.23−7.22 (m, 1H), 3.71 (s, 2H), 1.01 (br s, 2H); ¹³C

NMR (100 MHz, CDCl₃, ppm) δ 142.6, 141.8, 138.7, 129.8, 129.3,

128.4, 127.2, 126.5, 40.8; FT-IR (neat, cm⁻¹) ν 3060, 3031, 2937, 1603,

1580, 1498, 1454, 1443, 1185, 1157, 1074, 1031. Anal. Calcd for

C₁₉H₁₇N (259.34 g/mol): C, 87.99; H, 6.61; N, 5.40. Found: C, 87.79;

H, 6.70; N, 5.36.

General Procedure for the Arylation of sp³C−H Bonds of

Picolinamides. A 2-dram screw-cap vial was charged with Pd(OAc)₂

(5 mol %, 11 mg), CuBr₂(10 mol %, 22 mg), picolinamide (1 mmol),

aryl iodide (4 mmol), CsOAc (4 mmol, 794 mg), and tert-amyl alcohol

(0.5 mL). The resulting suspension was stirred at 140 °C for 24 h. The

reaction mixture was extracted with dichloromethane (3 × 4 mL). The

extracts were combined, ﬁltered through a pad of cotton, concentrated,

and then loaded onto a chromatography column with hexanes/ethyl

acetate mixture as eluent and subjected to column chromatography.

After concentration of the fractions containing the product, the residue

was dried under reduced pressure.

N-(3-(4-Methoxyphenyl)propyl)picolinamide (Table 3, Entry 1). A

2-dram screw-cap vial was charged with Pd(OAc)₂(5 mol %, 11 mg),

CuBr₂(10 mol %, 22 mg), N-propylpicolinamide (1 mmol, 199 mg), 1-

iodo-4-methoxybenzene (4 mmol, 936 mg), CsOAc (4 mmol, 794 mg),

and tert-amyl alcohol (0.5 mL). The resulting suspension was stirred at

140 °C for 24 h. After chromatography (hexane/ethyl acetate 70/30), a

yellowish oil (168 mg, 56% yield) was obtained: R_f= 0.19 (hexanes/

ethyl acetate 70/30); this compound is known;^4a¹H NMR (400 MHz,

CDCl₃, ppm) δ 8.51 (d, J = 4.6 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.09

(br s, 1H), 7.82−7.80 (m, 1H), 7.40−7.38 (m, 1H), 7.11 (d, J = 8.0 Hz,

2H), 6.81 (d, J = 8.0 Hz, 2H), 3.76 (s, 3H), 3.50−3.46 (m, 2H), 2.68−

2.64 (m, 2H), 1.97−1.94 (m, 2H).

N-(4-(4-Methoxyphenyl)butan-2-yl)picolinamide (Table 3, Entry

2). A 2-dram screw-cap vial was charged with Pd(OAc)₂(5 mol %, 11

mg), CuBr₂(10 mol %, 22 mg), N-(2-methylpropan-2-yl)picolinamide

(1 mmol, 221 mg), 1-iodo-4-methoxybenzene (4 mmol, 936 mg),

K₂CO₃(4 mmol, 794 mg), and tert-amyl alcohol (2.0 mL). The resulting

suspension was stirred at 140 °C for 24 h. After chromatography

(hexane/ethyl acetate 70/30), pale yellow oil (255 mg, 75% yield) was

obtained: R_f= 0.27 (hexanes/ethyl acetate 70/30); this compound is

known;^4a¹H NMR (400 MHz, CDCl₃, ppm) δ 8.49−8.47 (m, 1H),

8.17−8.16 (m, 1H), 7.92 (br d, J = 8.7 Hz, 1H), 7.79−7.75 (m, 1H),

Installation of the Propanamide Auxiliary: N-(8-p-Tolylnaphtha-

len-1-yl)propionamide (9). 8-p-Tolylnaphthalen-1-amine 6 (2.02 g, 8.7

mmol) and triethylamine (1.34 mL, 9.57 mol) were dissolved in

S

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7.36−7.33 (m, 1H), 7.09−7.05 (m, 2H), 6.78−6.75 (m, 2H), 4.25−4.15

(m, 1H), 3.70 (s, 3H), 2.61 (t, J = 8.2 Hz, 2H), 1.91−1.75 (m, 1H), 1.25

(d, J = 6.9 Hz, 3H).

picolinamide (1 mmol), alkyl iodide (4−6 mmol), K₂CO₃(4 mmol, 794

mg), and water (0.30 mL). The resulting suspension was stirred at 120

°C for 24 h. The reaction mixture was diluted with dichloromethane (4

mL) and ﬁltered through a pad of cotton. The residue was then washed

with dichloromethane (2 × 4 mL). The organic solvents were combined,

concentrated, and then loaded onto a chromatography column with

hexanes/ethyl acetate mixture as eluent and subjected to column

chromatography. After concentration of the fractions containing the

product, the residue was dried under reduced pressure.

N-(1-(2,6-Dibutylphenyl)ethyl)picolinamide (Table 4, Entry 1). A 2-

dram screw-cap vial was charged with Pd(OAc)₂(10 mol %, 11 mg),

CuBr₂(20 mol %, 22 mg), N-(1-phenylethyl)picolinamide (1 mmol,

239 mg), n-butyl iodide (4 mmol, 736 mg), K₂CO₃(4 mmol, 552 mg),

and water (0.30 mL). The resulting suspension was stirred at 120 °C for

24 h. After chromatography (hexanes/ethyl acetate 70/30), light yellow

oil (336 mg, 99% yield) was obtained: R_f= 0.60 (hexanes/ethyl acetate

70/30); ¹H NMR (400 MHz, CDCl₃, ppm) δ 8.62 (br d, J=7.8 Hz, 1H),

8.52−8.50 (m, 1H), 8.19−8.17 (m, 1H), 7.80 (td, J = 7.5, 1.37 Hz, 1H),

7.40−7.36 (m, 1H), 7.14−7.10 (m, 2H), 7.06−7.04 (m, 1H), 5.76 (q, J =

7.3, 1H), 2.98−2.90 (m, 2H), 2.80−2.73 (m, 2H), 1.70−1.60 (m, 7H),

1.52−1.43 (m, 4H), 0.93 (t, J = 7.3 Hz, 1H); ¹³C NMR (100 MHz,

CDCl₃, ppm) δ 163.4, 150.1, 148.0, 141.0, 138.3, 137.4, 128.6, 127.1,

126.1, 122.2, 45.1, 34.5, 34.2, 23.2, 22.2, 14.1; FT-IR (neat, cm⁻¹) ν

2956, 1678, 1511, 1432, 1462, 1374, 1206. Anal. Calcd for C₂₂H₃₀N₂O

(338.49g/mol): C, 78.06; H, 8.93; N, 8.28. Found: C, 77.84; H, 8.92; N,

8.19.

N-(4-(4-Methoxyphenyl)-2-methylbutan-2-yl)picolinamide (Table

3, Entry 3). A 2-dram screw-cap vial was charged with Pd(OAc)₂(5 mol

%, 11 mg), CuBr₂(10 mol %, 22 mg), N-(2-methylpropan-2-

yl)picolinamide (1 mmol, 198 mg), 1-iodo-4-methoxybenzene (4

mmol, 936 mg), CsOAc (4 mmol, 794 mg), and tert-amyl alcohol (0.5

mL). The resulting suspension was stirred at 140 °C for 24 h. After

chromatography (hexane/ethyl acetate 70/30), pale yellow oil (278 mg,

91% yield) was obtained: R_f= 0.26 (hexanes/ethyl acetate 70/30); ¹H

NMR (400 MHz, CDCl₃, ppm) δ 8.50−8.49 (m, 1H), 8.17−8.15 (m,

1H), 8.00 (br s, 1H), 7.82−7.78 (m, 1H), 7.39−7.36 (m, 1H), 7.12−

7.09 (m, 2H), 6.80−6.76 (m, 2H), 3.73 (s, 3H), 2.61−2.56 (m, 2H),

2.16−2.12 (m, 2H), 1.50 (s, 6H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ

163.4, 157.8, 150.7, 147.9, 137.4, 134.4, 129.4, 126.0, 121.8, 113.8, 55.3,

53.5, 42.4, 29.9, 27.2; FT-IR (neat, cm⁻¹) ν 2963, 1675, 1510, 1464,

1247, 1178, 1033. Anal. Calcd for C₁₈H₂₂N₂O₂(298.38 g/mol): C,

72.46; H, 7.43; N, 9.39. Found: C, 72.15; H, 7.31; N, 9.37.

Ethyl 4-(3-(Picolinamido)cyclohexyl)benzoate (Table 3, Entry 4). A

2-dram screw-cap vial was charged with Pd(OAc)₂(5 mol %, 11 mg),

CuBr₂(10 mol %, 22 mg), N-cyclohexylpicolinamide (1 mmol, 194 mg),

ethyl 4-iodobenzoate (4 mmol, 1.10 g), CsOAc (4 mmol, 794 mg), and

tert-amyl alcohol (0.5 mL). The resulting suspension was stirred at 140

°C for 24 h. After chromatography (hexane/ethyl acetate 70/30), light

yellow powder (269 mg, 86%) was obtained: R_f= 0.35 (hexanes/ethyl

1

acetate 70/30); mp = 117−118 °C (hexanes); H NMR (400 MHz,

When n-butyl bromide (4 mmol, 548 mg) was used as an alkylating

agent, no product was detected by GC−MS.

CDCl₃, ppm) δ 8.45−8.43 (m, 1H), 8.13−8.11 (m, 1H), 7.97 (br d, J =

8.7 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.76−7.72 (m, 1H), 7.34−7.30 (m,

1H), 7.20 (d, J = 8.2 Hz, 2H), 4.27 (q, J = 6.9 Hz, 2H), 4.12−4.02 (m,

1H), 2.75−2.67 (m, 1H), 2.20 (d, J = 12.4 Hz, 1H), 2.07 (d, J = 12.4 Hz,

1H), 1.91−1.80 (m, 2H), 1.57−1.26 (m. 7H); ¹³C NMR (100 MHz,

CDCl₃, ppm) δ 167.7, 163.5, 151.4, 150.0, 148.1, 137.5, 129.8, 128.5,

126.9, 126.2, 122.3, 60.9, 48.7, 43.3, 40.4, 33.1, 32.7, 25.2, 14.4; FT-IR

(neat, cm⁻¹) ν 3371, 1713, 1656, 1519, 1276, 1110. Anal. Calcd for

C₂₁H₂₄N₂O₃(352.43 g/mol): C, 71.57; H, 6.86; N, 7.95. Found: C,

71.31; H, 6.69; N, 7.73.

N-(1-(2,6-Bis(4,4,4-triﬂuorobutyl)phenyl)ethyl)picolinamide

(Table 4, Entry 2). A 2-dram screw-cap vial was charged with Pd(OAc)₂

(5 mol %, 11 mg), CuBr₂(10 mol %, 22 mg), N-(1-phenylethyl)-

picolinamide (1 mmol, 229 mg), 1,1,1-triﬂuoro-4-iodobutane (4 mmol,

948 mg), K₂CO₃(4 mmol, 552 mg), and water (0.30 mL). The resulting

suspension was stirred at 120 °C for 24 h. After chromatography

(hexanes/ethyl acetate 70/30), light yellow oil (356 mg, 79% yield) was

obtained: R_f= 0.52 (hexanes/ethyl acetate 70/30); ¹H NMR (400 MHz,

CDCl₃, ppm) δ 8.54−8.51 (m, 2H), 8.17−8.14 (m, 1H), 7.84−7.80 (m,

1H), 7.42−7.39 (m, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz,

1H), 5.69 (q, J = 7.3 Hz, 3.10−3.01 (m, 1H), 2.88−2.80 (m, 2H), 2.29−

2.16 (m, 4H), 1.95−1.88 (m, 4H); ¹³C NMR (100 MHz, CDCl₃, ppm)

δ 163.4, 149.7, 148.1, 139.3, 138.8, 137.6, 129.1, 127.5, 127.2 (q, J =

276.1 Hz), 126.4, 122.2, 45.1, 33.8 (q, J = 28.8 Hz), 33.1, 24.1, 22.1; ¹⁹F

NMR (376 MHz, CDCl₃, ppm) δ 66.1; FT-IR (neat, cm⁻¹) ν 1678,

1512, 1465, 1434, 1388, 1251, 1132, 1005. Anal. Calcd for C₂₂H₂₄F₆N₂O

(446.43g/mol): C, 59.19; H, 5.42; N, 6.27. Found: C, 59.28; H, 5.48; N,

6.24.

N-(4-(3-Methoxybenzyl)-5-(3-methoxyphenyl)-2,4-dimethylpen-

tan-2-yl)picolinamide (A) and N-(5-(3-Methoxyphenyl)-2,4,4-trime-

thylpentan-2-yl)picolinamide (B) (Table 3, Entry 5). A 2-dram screw-

cap vial was charged with Pd(OAc)₂(10 mol %, 22 mg), CuBr₂(20 mol

%, 44 mg), N-(2,4,4-trimethylpentan-2-yl)picolinamide (1 mmol, 245

mg), 1-iodo-4-methoxybenzene (4 mmol, 936 mg), K₂CO₃(6 mmol,

794 mg), and tert-amyl alcohol (0.5 mL). The resulting suspension was

stirred at 140 °C for 24 h. The following products were obtained after

column chromatography in hexanes/ethyl acetate 70/30.

Product A was obtained as a light yellow oil (138 mg, 29% yield): R_f=

0.69 (hexanes/ethyl acetate 70/30), ¹H NMR (400 MHz, CDCl₃, ppm)

δ 8.49 (m, 1H), 8.17−8.15 (m, 2H), 7.82−7.79 (m, 1H), 7.38−7.35 (m,

1H), 7.17−7.14 (m, 2H), 6.76−6.72 (m, 4H), 6.68−6.67 (m, 2H), 3.76

(s, 6H), 2.83 (d, J = 13.0 Hz, 2H), 2.60 (d, J = 13.0, 2H), 2.10 (s, 2H),

1.56 (s, 6H), 1.08 (s, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 163.3,

159.1, 150.8, 147.9, 140.5, 137.5, 134.4, 128.6, 125.9, 123.7, 121.7, 116.9,

111.3, 55.2, 54.7, 48.3, 48.0, 39.0, 29.9, 24.8; FT-IR (neat, cm⁻¹) ν 2955,

1679, 1582, 1521, 1488, 1263, 1154, 1043. Anal. Calcd for C₂₈H₃₄N₂O₃

(446.58 g/mol): C, 75.31; H, 7.67; N, 6.27. Found: C, 74.96; H, 7.67; N,

6.22.

N-(1-(2,6-Diisobutylphenyl)ethyl)picolinamide (Table 4, Entry 3).

A 10-mL Kontes ﬂask was charged with Pd(OAc)₂(10 mol %, 22 mg),

CuBr₂(20 mol %, 44 mg), N-(1-phenylethyl)picolinamide (1 mmol,

239 mg), 1-iodo-2-methylpropane (6 mmol, 1.10 g), K₂CO₃(4 mmol,

552 mg), and water (0.30 mL). The resulting suspension was stirred at

120 °C for 24 h. After chromatography (hexane/ethyl acetate 70/30),

light yellow oil (301 mg, 84% yield) was obtained: R_f= 0.39 (hexanes/

ethyl acetate 70/30); ¹H NMR (400 MHz, CDCl₃, ppm) δ 8.61 (br d, J

= 8.0 Hz, 1H) 8.52−8.51 (m, 1H), 8.19−8.17 (m, 1H), 7.79 (td, J = 7.5,

1.7 Hz, 1H), 7.39−7.36 (m, 1H), 7.12−7.10 (m, 1H), 7.05−7.04 (m,

2H), 5.76 (q, J = 8.0 Hz, 1H), 2.91 (dd, J = 13.8, 6.9 Hz, 2H), 2.62 (dd, J

= 13.8, 5.7 Hz, 2H), 2.04 (m, 2H), 1.67 (d, J = 6.9 Hz, 3H), 1.00 (d, J =

6.9 Hz, 6H), 0.96 (d, J = 6.9 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃,

ppm) δ 163.4, 150.1, 148.0, 139.7, 139.2, 137.4, 129.3, 126.4, 126.1,

122.2, 45.2, 43.3, 29.7, 23.0, 22.6, 22.3; FT-IR (neat, cm⁻¹) ν 2954, 1677,

1509, 1464, 1432, 1383. Anal. Calcd for C₂₂H₃₀N₂O (338.49 g/mol): C,

78.06; H, 8.93; N, 8.28. Found: C, 78.03; H, 9.11; N, 8.37.

N-(1-(2,6-Diphenethylphenyl)ethyl)picolinamide (Table 4, Entry

4). A 2-dram screw-cap vial was charged with Pd(OAc)₂(10 mol %, 22

mg), CuBr₂(20 mol %, 44 mg), N-(1-phenylethyl)picolinamide (1

mmol, 228 mg), (2-iodoethyl)benzene (4 mmol, 984 mg), K₂CO₃(4

mmol, 552 mg), and water (0.30 mL). The resulting suspension was

stirred at 120 °C for 24 h. After chromatography (hexane/ethyl acetate

70/30), light yellow oil (375 mg, 86% yield) was obtained: R_f= 0.33

Product B was obtained as a colorless oil (46 mg, 13%): R_f= 0.64

1

(hexane/ethyl acetate 70/30); H NMR (400 MHz, CDCl₃, ppm) δ

8.51−8.49 (m, 1H), 8.18−8.16 (m, 1H), 8.14 (br s, 1H), 7.83−7.79 (m,

1H), 7.38−7.35 (m, 1H), 7.17−7.14 (m, 1H), 6.75−6.71 (m, 2H),

6.68−6.72 (m, 1H), 3.77 (s, 3H), 2.58 (s, 2H), 1.97 (s, 2H), 1.57 (s,

6H), 1.01 (s, 6H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 163.2, 159.0,

150.8, 147.9, 140.62, 137.4, 128.5, 125.9, 123.5, 121.7, 116.9, 111.1, 55.2,

54.7, 51.2, 51.1, 35.5, 29.6, 27.8; FT-IR (neat, cm⁻¹) ν 2916, 1679, 1583,

1520, 1488, 1463, 1264, 1045. Anal. Calcd for C₂₁H₂₈N₂O₂(340.46 g/

mol): C, 74.08; H, 8.29; N, 8.23. Found: C, 73.79; H, 8.28; N, 8.11.

General Procedure for the Alkylation of sp²and sp³C−H Bonds of

Picolinamides. A Kontes ﬂask or a 2-dram screw-cap vial was charged

with Pd(OAc)₂(10 mol %, 22 mg), CuBr₂(20 mol %, 44 mg),

T

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The Journal of Organic Chemistry

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1

(hexanes/ethyl acetate 70/30); H NMR (400 MHz, CDCl₃, ppm) δ

for C₂₅H₃₂N₂O (376.53 g/mol): C, 79.75; H, 8.57; N, 7.44. Found: C,

79.89; H, 8.21; N, 7.48.

8.68 (br d, J = 7.8 Hz, 1H), 8.45−8.43 (m, 1H), 8.20−8.18 (m, 1H), 7.77

(td, J = 7.8, 1.8 Hz, 1H), 7.36−7.27 (m, 9H), 7.22−7.13 (m, 5H), 5.88

(q, J = 7.8 Hz, 1H), 3.31−2.99 (m, 6H), 1.68 (d, J = 6.9 Hz, 3H); ¹³C

NMR (100 MHz, CDCl₃, ppm) δ 163.6, 150.0, 148.2, 142.1, 140.2,

138.8, 137.6, 129.2, 128.7, 128.6, 127.5, 126.4, 126.2, 122.4, 45.4, 38.5,

36.6, 22.2; FT-IR (neat, cm⁻¹) ν 1676, 1509, 1453, 1432. Anal. Calcd for

C₃₀H₃₀N₂O (434.57 g/mol): C, 82.91; H, 6.96; N, 6.45. Found: C,

82.71; H, 7.22; N, 6.41.

N-(1-(2,6-Dibenzylphenyl)ethyl)picolinamide (Table 4, Entry 5). A

2-dram screw-cap vial was charged with Pd(OAc)₂(5 mol %, 11 mg),

CuBr₂(10 mol %, 22 mg), N-(1-phenylethyl)picolinamide (1 mmol,

228 mg), benzyl iodide (4 mmol, 872 mg), K₂CO₃(4 mmol, 552 mg),

and water (0.30 mL). The resulting suspension was stirred at 120 °C for

24 h. After chromatography (hexanes/ethyl acetate 70/30), light yellow

oil (349 mg, 85% yield) was obtained: R_f= 0.43 (hexanes/ethyl acetate

70/30); ¹H NMR (400 MHz, CDCl₃, 50 °C, ppm) δ 8.34 (br d, J = 6.87

Hz, 1H), 8.30−8.28 (m, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.71 (td, J = 7.5,

1.7 Hz, 1H), 7.28−7.26 (m, 1H), 7.19−7.03 (m, 13H), 5.72 (q, J = 7.5

Hz, 1H), 4.45 (d, J = 16.0 Hz, 2H), 4.21 (d, J = 16.0 Hz, 2H), 1.24 (d, J =

7.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 163.6, 149.8, 147.9,

141.2, 139.9, 138.9 (br), 137.1, 130.7 (br), 129.0, 128.4, 127.3, 125.9,

125.8, 121.9, 45.6, 40.1 (br), 20.6; FT-IR (neat, cm⁻¹) ν 3381, 1676,

1497, 1462, 1431. Anal. Calcd for C₂₈H₂₆N₂O (406.52 g/mol): C, 82.73;

H, 6.45; N, 6.89. Found: C, 82.54; H, 6.44; N, 6.79.

N-(2-(2,6-Dibutylphenyl)propan-2-yl)picolinamide (A) and N-(2-

(2-Butylphenyl)propan-2-yl)picolinamide (B) (Table 4, Entry 6). A 2-

dram screw-cap vial was charged with Pd(OAc)₂(5 mol %, 11 mg),

CuBr₂(10 mol %, 22 mg), N-(2-phenylpropan-2-yl)picolinamide (1

mmol, 224 mg), iodobutane (6 mmol, 1.10 g), K₂CO₃(4 mmol, 552

mg), and water (0.30 mL). The resulting suspension was stirred at 120

°C for 24 h. After chromatography (hexane/ethyl acetate 70/30), two

products were obtained.

Product A was obtained as a light yellow oil (178 mg, 54% yield): R_f=

0.44 (hexanes/ethyl acetate 70/30); ¹H NMR (400 MHz, CDCl₃, ppm)

δ 8.54 (br s, 1H), 8.51−8.49 (m, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.80 (td, J

= 9.2, 1.4 Hz, 1H), 7.40−7.36 (m, 1H), 7.10−7.02 (m, 3H), 2.90−2.86

(m, 4H), 2.08 (s, 6H), 1.56−1.48 (m, 4H), 1.29−1.20 (m, 4H), 0.74 (t, J

= 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 162.1, 150.9,

147.8, 141.9, 141.5, 137.4, 130.5, 126.5, 125.9, 121.8, 59.1, 36.5, 35.5,

31.0, 23.3, 14.0; FT-IR (neat, cm⁻¹) ν 2956, 1678, 1510, 1463. Anal.

Calcd for C₂₃H₃₂N₂O (352.51 g/mol): C, 78.36; H, 9.15; N, 7.95.

Found: C, 78.12; H, 9.31; N, 7.83.

Product B was obtained as a light yellow oil (38 mg, 14% yield): R_f=

0.31 (hexanes/ethyl acetate 70/30); ¹H NMR (400 MHz, CDCl₃, ppm)

δ 8.51−8.47 (m, 2H), 8.14−8.12 (m, 1H), 7,82−7.79 (m, 1H), 7.50−

7.48 (m, 1H), 7.41−7.37 (m, 1H), 7.23−7.15 (m, 3H), 2.82−2.78 (m,

2H), 1.92 (s, 6H), 1.47−1.40 (m, 2H), 1.18−1.12 (m, 2H), 0.61 (t, J =

7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 162.8, 150.7, 147.8,

143.2, 140.8, 137.4, 131.6, 127.4, 127.2, 126.0, 125.7, 121.8, 56.3, 34.8,

33.8, 29.0, 23.4, 13.9; signal for one carbon could not be located; FT-IR

(neat, cm⁻¹) ν 2930, 1678, 1511, 1463, 1432; HRMS (m/z) [M⁺] calcd

for C₁₉H₂₄N₂O 296.1889, found 296.1883, error = −2.0 ppm.

N-(2,6-Dicyclohexylbenzyl)picolinamide (A) and N-(2-

Cyclohexylbenzyl)picolinamide (B) (Table 4, Entry 7). A 2-dram

screw-cap vial was charged with Pd(OAc)₂(10 mol %, 22 mg), CuBr₂

(20 mol %, 44 mg), N-benzylpicolinamide (1 mmol, 223 mg),

iodocyclohexane (4 mmol, 840 mg), K₂CO₃(4 mmol, 552 mg), and

water (0.30 mL). The resulting suspension was stirred at 120 °C for 24

h. After chromatography (hexane/ethyl acetate 80/20), two products

were obtained.

Product B was obtained as a light yellow oil (62 mg, 20% yield): R_f=

0.50 (hexanes/ethyl acetate 80/20); ¹H NMR (400 MHz, CDCl₃, ppm)

δ 8.50−8.48 (m, 1H), 8.25−8.19 (m, 2H), 7.86−7.82 (m, 1H), 7.42−

7.38 (m, 1H), 7.33−7.30 (m, 1H), 7.19−7.15 (m, 1H), 4.71 (d, J = 5.5

Hz, 2H), 2.81−2.74 (m, 1H), 1.81−1.70 (m, 5H), 1.49−1.19 (m, 5H;

¹³C NMR (100 MHz, CDCl₃, ppm) δ 164.9, 149.9, 148.2, 146.6, 137.4,

134.7, 129.3, 128.2, 126.6, 126.2, 126.0, 122.3, 41.5, 39.7, 34.5, 27.0,

26.3; FT-IR (neat, cm⁻¹) ν 2926, 2851, 1674, 1568, 1522, 1241. Anal.

Calcd for C₁₉H₂₂N₂O (294.39 g/mol): C, 77.52; H, 7.53; N, 9.52.

Found: C, 77.13; H, 7.67; N, 9.40.

N-(2-Cyclohexyl-6-methoxybenzyl)picolinamide (Table 4, Entry 8).

A 2-dram screw-cap vial was charged with Pd(OAc)₂(10 mol %, 22 mg),

CuBr₂(20 mol %, 44 mg), N-(2-methoxybenzyl)picolinamide (1 mmol,

217 mg), iodocyclohexane (4 mmol, 840 mg), K₂CO₃(4 mmol, 552

mg), and water (0.30 mL). The resulting suspension was stirred at 120

°C for 24 h. After chromatography (hexanes/ethyl acetate 70/30), light

yellow oil (47 mg, 14% yield) was obtained: R_f= 0.39 (hexanes/ethyl

1

acetate 70/30); H NMR (400 MHz, CDCl₃, ppm) δ 8.49−8.47 (m,

1H), 8.23−8.20 (m, 1H), 7.81 (td, J = 9.5, 2.0 Hz, 1H), 7.38−7.35 (m,

1H), 7.27−7.23 (m, 1H), 6.93−6.91 (m, 1H), 6.77−6.74 (m, 1H), 4.76

(d, J = 5.5 Hz, 2H), 3.87 (s, 3H), 3.02−2.97 (m, 1H), 1.78−1.72 (m,

5H), 1.51−1.36 (m, 4H), 1.27−1.21 (m, 1H); ¹³C NMR (100 MHz,

CDCl₃, ppm) δ 163.7, 158.3, 150.4, 148.4, 148.1, 137.3, 128.7, 125.9,

123.5, 122.3, 118.8, 108.0, 55.7, 39.9, 34.6, 34.4, 27.0, 26.3; FT-IR (neat,

cm⁻¹) ν 2926, 1674, 1582, 1518, 1464, 1249, 1136, 1096. Anal. Calcd for

C₂₀H₂₄N₂O₂(324.42 g/mol): C, 74.04; H, 7.46; N, 8.64; O, 9.86 Found:

C, 73.76; H, 7.50; N, 8.49.

N-(8-Octylnaphthalen-1-yl)picolinamide (Table 4, Entry 9). A 2-

dram screw-cap vial was charged with Pd(OAc)₂(5 mol %, 11 mg),

CuBr₂(10 mol %, 22 mg), N-(naphthalen-1-yl)picolinamide (1 mmol,

217 mg), octyl iodide (4 mmol, 960 mg), CsOAc (3 mmol, 594 mg), and

tert-amyl alcohol (0.50 mL). The resulting suspension was stirred at 140

°C for 24 h. After chromatography (hexane/ethyl acetate 70/30), light

yellow oil (153 mg, 49% yield) was obtained: R_f= 0.33 (hexanes/ethyl

1

acetate 70/30); H NMR (400 MHz, CDCl₃, ppm) δ 10.56 (s, 1H),

8.64−8.62 (m, 1H), 8.39−8.36 (m, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.89

(td, J = 7.6, 1.6 Hz, 1H), 7.77−7.72 (m, 2H), 7.52−7.45 (m, 2H), 7.38−

7.30 (m, 2H), 3.30−3.26 (m, 2H), 1.68−1.61 (m, 2H), 1.27−1.13 (m,

10H), 0.86 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ

162.5, 150.3, 148.1, 137.9, 137.8, 136.3, 132.7, 126.9, 128.0, 127.9, 127.5,

126.6, 125.6, 125.2, 122.8, 37.8, 32.9, 31.9, 29.8, 29.6, 29.4, 22.8, 14.3;

FT-IR (neat, cm⁻¹) ν 2926, 1686, 1522, 1498, 1431, 1339. Anal. Calcd

for C₂₄H₂₈N₂O (360.49 g/mol): C, 79.96; H, 7.83; N, 7.77. Found: C,

79.78; H, 7.93; N, 7.79.

N-(2-Methylnonan-2-yl)picolinamide (Table 4, Entry 10). A 2-dram

screw-cap vial was charged with Pd(OAc)₂(10 mol %, 11 mg), CuBr₂

(20 mol %, 22 mg), N-(tert-pentyl)picolinamide (1 mmol, 192 mg),

iodopentane (4 mmol, 792 mg), K₂CO₃(4 mmol, 552 mg), pivalic acid

(2 mmol, 202 mg), and tert-amyl alcohol (0.7 mL). The resulting

suspension was stirred at 110 °C for 24 h. After chromatography

(hexanes/ethyl acetate 80/20), colorless oil (67 mg, 27% yield) was

obtained: R_f= 0.31 (hexanes/ethyl acetate 80/20); ¹H NMR (400 MHz,

CDCl₃, ppm) δ 8.53−8.52 (m, 1H), 8.19−8.16 (m, 1H), 7.97 (br s, 1H),

7.83 (td, J = 9.6, 1.8 Hz, 1H), 7.41−7.38 (m, 1H), 1.88−1.79 (m, 2H),

1.46 (s, 6H), 1.34−1.26 (m, 10H), 0.87 (t, J = 6.9 Hz, 3H) ¹³C NMR

(100 MHz, CDCl₃, ppm) δ 163.3, 150.9, 147.8, 137.4, 125.9, 121.7, 53.6,

40.7, 32.0, 30.1, 29.4, 26.9, 24.3, 22.7, 14.2; FT-IR (neat, cm⁻¹) ν 2926,

1681, 1520, 1464, 1432, 1363, 1287. Anal. Calcd for C₁₆H₂₆N₂O (262.39

g/mol): C, 73.24; H, 9.99; N, 10.68. Found: C, 73.04; H, 10.04; N,

10.38.

General Procedure for the Alkylation of sp²C−H Bonds of 8-

Aminoquinoline Amides. A 2−dram screw−capped vial was charged

with Pd(OAc)₂(5 mol %), K₂CO₃(2.5 equiv), substrate, pivalic acid (20

mol %), and alkyl bromide or iodide (3−4 equiv). The tert-amyl alcohol

(0.7−3.0 mL) solvent was added and the resulting mixture was stirred at

100−110 °C for 12−96 h. The reaction mixture was allowed to cool to

room temperature and diluted with ethyl acetate (10 mL), followed by

washing with water (10 mL). The aqueous layer was extracted with ethyl

Product A was obtained as a light yellow oil (42 mg, 11% yield): R_f=

0.31 (hexanes/ethyl acetate 80/20); ¹H NMR (400 MHz, CDCl₃, ppm)

δ 8.45−8.44 (m. 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.89−7.82 (m, 2H),

7.40−7.37 (m, 1H), 7.30−7.27 (m, 1H), 7.18−7.16 (m, 1H), 4.73 (d, J =

4.6 Hz, 2H), 2.83−2.75 (m, 2H), 1.80−1.69 (m, 12H), 1.49−1.18 (m,

10H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 163.7, 149.9, 148.7, 147.5,

137.4, 131.4, 128.3, 126.2, 124.2, 122.2, 40.5, 36.6, 35.0, 27.1, 26.3; FT-

IR (neat, cm⁻¹) ν 2925, 2850, 1673, 1521, 1568, 1433, 1242. Anal. Calcd

U

dx.doi.org/10.1021/jo4013628 | J. Org. Chem. XXXX, XXX, XXX−XXX

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acetate (3 × 10 mL). The organic layers were combined, dried over

MgSO₄, and ﬁltered. The ﬁltrate was concentrated under vacuum. The

crude product was puriﬁed by ﬂash column chromatography.

124.3 (q, J_C−F= 3.5 Hz), 123.9 (q, J_C−F= 271.5 Hz), 122.4, 121.8, 116.9,

38.9; ¹⁹F NMR (376 MHz, CDCl₃, ppm) δ −62.3 (s); FT-IR (neat,

cm⁻¹) ν 3361, 1674, 1525, 1485. Anal. Calcd for C₂₄H₁₇F₃N₂O (406.40

g/mol): C, 70.93; H, 4.22; N, 6.89. Found: C, 70.83; H, 4.33; N 6.69.

2,6-Dibenzyl-4-methoxy-N-(quinolin-8-yl)benzamide (Table 5,

Entry 5). Pd(OAc)₂(8.3 mg, 0.037 mmol), 4-methoxy-N-(quinolin-8-

yl)benzamide (206 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol),

pivalic acid (14.8 mg, 0.15 mmol), and benzyl bromide (380 mg, 2.22

mmol) were dissolved in tert-amyl alcohol (0.7 mL). The resulting

mixture was stirred at 110 °C for 15 h. After column chromatography

(toluene/ethyl acetate 40/1), 198 mg (58%) of crystalline material was

obtained. R_f= 0.33 (toluene/ethyl acetate 40/1), mp =137−138 °C

(hexanes); ¹H NMR (500 MHz, CDCl₃, ppm) δ 9.74 (s, 1H), 8.92 (dd, J

= 7.5, 1.1 Hz, 1H), 8.61 (dd, J = 4.1, 1.3 Hz, 1H), 8.14 (dd, J = 8.2, 1.4

Hz, 1H), 7.60−7.51 (m, 2H), 7.42−7.38 (m, 1H), 7.20−7.17 (m, 4H),

7.14−7.10 (m, 4H), 7.06−7.01 (m, 2H), 6.59 (s, 2H), 4.09 (s, 4H), 3.70

(s, 3H); ¹³C NMR (400 MHz, CDCl₃, ppm) δ 168.5, 159.9, 148.0,

140.1, 140.0, 138.4, 136.1, 134.4, 131.1, 129.2, 128.4, 127.9, 127.4, 126.1,

121.8, 121.5, 116.6, 113.5, 55.2, 39.4; FT-IR (neat, cm⁻¹) ν 3344, 1669,

1521, 1485. Anal. Calcd for C₃₁H₂₆N₂O₂(458.55 g/mol): C, 81.20; H,

5.72; N, 6.11. Found: C, 80.94; H, 5.73; N 6.10.

2-Benzyl-6-methoxy-N-(quinolin-8-yl)benzamide (Table 5, Entry

1). Pd(OAc)₂(8.3 mg, 0.037 mmol), 2-methoxy-N-(quinolin-8-

yl)benzamide (206 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol),

pivalic acid (14.8 mg, 0.148 mmol), and benzyl bromide (380 mg, 2.22

mmol) were dissolved in tert-amyl alcohol (0.7 mL). The resulting

mixture was stirred at 110 °C for 20 h. After column chromatography

(toluene/ethyl acetate 70/1), 166 mg (61% yield) of a crystalline

material was obtained: R_f= 0.19 (toluene/ethyl acetate 70/1); mp =

137−139 °C (hexanes); ¹H NMR (500 MHz, CDCl₃, ppm) δ 9.98 (s,

1H), 8.99−8.95 (dd, J = 7.7, 1.3 Hz, 1H), 8.71−8.68 (dd, J = 4.0, 1.3 Hz,

1H), 8.17−8.14 (dd, 1H, J = 8.3, 1.2 Hz), 7.61−7.57 (m, 1H), 7.55−7.52

(m, 1H), 7.44−7.41 (m, 1H), 7.33−7.29 (m, 1H), 7.21−7.17 (m, 2H),

7.13−7.09 (m, 2H), 7.04−7.00 (m, lH), 6.89−6.81 (m, 2H), 4.13 (s,

2H), 3.84 (s, 3H); ¹³C NMR (500 MHz, CDCl₃, ppm) δ 166.4, 156.5,

148.1, 140.5, 140.4, 138.5, 136.2, 134.7, 130.3, 129.2, 128.3, 128.0, 127.5,

127.2, 126.0, 122.6, 121.7, 121.5, 116.8, 109.0, 55.9, 38.9; FT-IR (neat,

cm⁻¹) ν 3330, 1670, 1525, 1483. Anal. Calcd for C₂₄H₂₀N₂O₂(368.43 g/

mol): C, 78.24; H, 5.47; N, 7.60. Found: C, 78.27; H, 5.54; N 7.46.

2,6-Dibenzyl-4-bromo-N-(quinolin-8-yl)benzamide (Table 5, Entry

2). Pd(OAc)₂(8.3 mg, 0.037 mmol), 4-bromo-N-(quinolin-8-yl)-

benzamide (242 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol), pivalic

acid (14.8 mg, 0.15 mmol), and benzyl bromide (380 mg, 2.22 mmol)

were dissolved in tert-amyl alcohol (0.7 mL). The resulting mixture was

stirred at 110 °C for 12 h. After column chromatography (toluene), 285

mg (76%) of a crystalline material was obtained: R_f= 0.27 (toluene); mp

= 118−119 °C (hexanes); ¹H NMR (500 MHz, CDCl₃, ppm) δ 9.74 (s,

1H), 8.91−8.87 (dd, J = 7.4, 1.5 Hz, 1H), 8.63−8.60 (dd, J = 4.3, 1.5 Hz,

1H), 8.17−8.13 (dd, J = 8.6, 1.7 Hz, 1H), 7.61−7.53 (m, 2H), 7.44−7.40

(m, 1H), 7.22 (s, 2H), 7.18−7.11 (m, 8H), 7.06−7.02 (m, 2H), 4.07 (s,

4H); ¹³C NMR (400 MHz, CDCl₃, ppm) δ 167.5, 148.2, 140.4, 139.3,

138.4, 136.8, 136.2, 134.0, 131.0, 129.21, 128.6, 127.9, 127.3, 126.4,

123.5, 122.2, 121.7, 116.8, 39.0; FT-IR (neat, cm⁻¹) ν 3358, 1677, 1524,

1485. Anal. Calcd for C₃₀H₂₃BrN₂O (507.42 g/mol): C, 71.01; H, 4.57;

N; 5.52. Found: C, 71.19; H, 4.52; N 5.48.

2,6-Dibenzyl-4-tert-butyl-N-(quinolin-8-yl)benzamide (Table 5,

Entry 3). Pd(OAc)₂(8.3 mg, 0.037 mmol), 4-tert-butyl-N-(quinolin-8-

yl)benzamide (225 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol),

pivalic acid (14.8 mg, 0.15 mmol), and benzyl bromide (380 mg, 2.22

mmol) were dissolved in tert-amyl alcohol (0.7 mL). The resulting

mixture was stirred at 100 °C for 20 h. After column chromatography

(toluene/ethyl acetate 100/1 to 50/1), 318 mg (88% yield) of a

crystalline material was obtained: R_f= 0.22 (toluene/ethyl acetate 70/

1); mp = 136−137 °C (hexanes); ¹H NMR (500 MHz, CDCl₃, ppm) δ

9.64 (s, 1H), 8.93−8.90 (dd, J = 7.4, 1.3 Hz, 1H), 8.57−8.54 (dd, J = 4.1,

1.7 Hz, 1H), 8.14−8.11 (dd, J = 8.6, 1.6 Hz, 1H), 7.59−7.51 (m, 2H),

7.40−7.37 (m, 1H), 7.17−7.12 (m, 6H), 7.10−7.05 (m, 4H), 7.01− 6.97

(m, 2H), 4.10 (s, 4H), 1.25 (s, 9H); ¹³C NMR (400 MHz, CDCl₃, ppm)

δ 168.7, 152.2, 148.0, 140.5, 138.4, 137.6, 136.1, 135.4, 134.4, 129.1,

128.3, 127.9, 127.4, 125.9, 125.4, 121.9, 121.5, 116.7, 39.6, 34.7, 31.3;

FT-IR (neat, cm⁻¹) ν 3363, 1676, 1521, 1485. Anal. Calcd for

C₃₄H₃₂N₂O (507.42 g/mol): C, 84.26; H, 6.66; N, 5.78. Found: C,

84.26; H, 6.68; N 5.82.

2,6-Dibenzyl-4-methoxy-3-methyl-N-(quinolin-8-yl)benzamide

(Table 5, Entry 6). Pd(OAc)₂(8.3 mg, 0.037 mmol), 4-methoxy-3-

methyl-N-(quinolin-8-yl)benzamide (216 mg, 0.74 mmol), K₂CO₃(256

mg, 1.85 mmol), pivalic acid (14.8 mg, 0.15 mmol), and benzyl bromide

(380 mg, 2.22 mmol) were dissolved in tert-amyl alcohol (1.0 mL). The

resulting mixture was stirred at 110 °C for 24 h. After column

chromatography (toluene/ethyl acetate 40/1), 258 mg (74%) of

crystalline material was obtained: TLC R_f= 0.35 (toluene/ethyl acetate

1

40/1); mp = 138−139 °C (hexanes); H NMR (500 MHz, CDCl₃,

ppm) δ 9.70 (s, 1H), 8.87 (dd, J = 7.5, 1.3 Hz, 1H,), 8.53 (dd, J = 4.3, 1.6

Hz, 1H), 8.09 (dd, J = 8.2, 1.5 Hz, 1H), 7.56−7.46 (m, 2H), 7.39−7.34

(m, 1H), 7.25−7.13 (m, 3H), 7.13−7.08 (m, 5H), 7.07−6.96 (m, 2H),

6.63 (s, 1H), 4.15 (s, 2H), 4.11 (s, 2H), 3.76 (s, 3H), 2.07 (s, 3H).¹³C

NMR (400 MHz, CDCl₃, ppm) δ 169.2, 158.3, 147.9, 140.6, 140.0,

138.4, 136.6, 136.3, 136.0, 134.4, 132.1, 129.1, 128.4, 128.3, 128.3, 127.8,

127.3, 126.0, 125.6, 124.5, 121.7, 121.4, 116.5, 110.2, 55.5, 39.5, 36.9,

11.9; FT-IR (neat, cm⁻¹) ν 3353, 1671, 1521, 1482; HRMS (m/z) [M⁺]

calcd for C₃₂H₂₈N₂O₂472.2151, found 472.2152, error = 0.2 ppm.

4-tert-Butyl-2,6-diethyl-N-(quinolin-8-yl)benzamide (Table 5,

Entry 7). Pd(OAc)₂(8.3 mg, 0.037 mmol), 4-tert-butyl-N-(quinolin-8-

yl)benzamide (225 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol),

pivalic acid (14.8 mg, 0.15 mmol), and iodoethane (346 mg, 2.22 mmol)

were dissolved in tert-amyl alcohol (1.0 mL). The resulting mixture was

stirred at 110 °C for 20 h. After column chromatography (toluene/ethyl

acetate 50/1), 240 mg (90%) of crystalline material was obtained: R_f=

1

0.33 (toluene/ethyl acetate 50/1); mp = 125−127 °C (hexanes); H

NMR (500 MHz, CDCl₃, ppm) δ 9.94 (s, 1H), 9.00 (dd, J = 7.5, 1.3 Hz,

1H), 8.72 (dd, J = 4.4, 1.6 Hz, 1H), 8.19−8.15 (dd, J = 8.5, 1.7 Hz, 1H),

7.63−7.54 (m, 2H), 7.45−7.41 (m, 1H), 7.19−7.16 (m, 2H), 2.78−2.71

(m, 4H), 1.35 (s, 9H), 1.25 (t, J = 7.8 Hz, 6H); ¹³C NMR (400 MHz,

CDCl₃, ppm) δ 169.3, 152.2, 148.3, 140.4, 138.6, 136.3, 134.6, 134.5,

128.1, 127.5, 123.3, 121.8, 121.7, 116.8, 34.8, 31.4, 26.9, 16.2; FT-IR

(neat, cm⁻¹) ν 3341, 1673, 1520, 1487. Anal. Calcd for C₂₄H₂₈N₂O

(360.49 g/mol): C, 79.96; H, 7.83; N, 7.77. Found: C, 79.81; H, 7.88; N

7.66.

2-Benzyl-N-(quinolin-8-yl)-5-(triﬂuoromethyl)benzamide (Table

5, Entry 4). Pd(OAc)₂(8.3 mg, 0.037 mmol), N-(quinolin-8-yl)-3-

(triﬂuoromethyl)benzamide (234 mg, 0.74 mmol), K₂CO₃(256 mg,

1.85 mmol), pivalic acid (14.8 mg, 0.15 mmol), and benzyl bromide

(380 mg, 2.22 mmol) were dissolved in tert-amyl alcohol (0.7 mL). The

resulting mixture was stirred at 110 °C for 20 h. After column

chromatography (hexanes/ethyl acetate 10/1), 212 mg (71%) of

crystalline material was obtained: R_f= 0.27 (hexanes/ethyl acetate 10/

1); mp = 124−126 °C (hexanes); ¹H NMR (500 MHz, CDCl₃, ppm) δ

10.11 (s, 1H), 8.91−8.87 (d, J = 7.1 Hz, 1H), 8.75−8.72 (dd, J = 4.1, 1.5

Hz, 1H), 8.21−8.17 (dd, J = 8.5, 1.2 Hz, 1H), 7.90 (s, 1H), 7.67−7.57

(m, 3H), 7.48−7.45 (m, 1H), 7.40−7.37 (m, 1H), 7.21−7.18 (m, 4H),

7.12−7.08 (m, 1H), 4.34 (s, 2H); ¹³C NMR (400 MHz, CDCl₃, ppm) δ

196.8, 148.4, 143.8, 139.6, 138.5, 137.6, 136.4, 134.3, 131.5, 129.3, 128.9

(q, J_C−F= 32.0 Hz), 128.6, 128.5, 128.0, 127.0 (q, J_C−F= 3.5 Hz), 126.5,

4-tert-Butyl-2,6-diisobutyl-N-(quinolin-8-yl)benzamide (Table 5,

Entry 8). Pd(OAc)₂(8.3 mg, 0.037 mmol), 4-tert-butyl-N-(quinolin-8-

yl)benzamide (225 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol),

pivalic acid (14.8 mg, 0.15 mmol), and 1-iodo-2-methylpropane (408

mg, 2.22 mmol) were dissolved in tert-amyl alcohol (1.0 mL). The

resulting mixture was stirred at 110 °C for 40 h. After column

chromatography (toluene/ethyl acetate 50/1), 229 mg (75%) of

crystalline material was obtained: R_f= 0.37 (toluene/ethyl acetate 50/

1); mp = 114−116 °C (hexanes); ¹H NMR (500 MHz, CDCl₃, ppm) δ

9.86 (s, 1H), 8.98 (dd, J = 7.5, 1.4 Hz, 1H), 8.71 (dd, J = 4.2, 1.6 Hz, 1H),

8.18 (dd, J = 8.4, 1.6 Hz, 1H), 7.64−7.54 (m, 2H), 7.46−7.42 (m, 1H),

7.10 (s, 2H) 2.59 (d, J = 7.3 Hz, 4H), 2.04−1.93 (m, 2H), 1.35 (s, 9H),

0.85 (d, J = 6.7 Hz, 12H); ¹³C NMR (400 MHz, CDCl₃, ppm) δ 169.3,

151.1, 148.2, 138.6, 137.8, 136.3, 135.7, 134.6, 128.1, 127.5, 124.7, 121.7,

V

dx.doi.org/10.1021/jo4013628 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

121.6, 116.7, 43.0, 34.6, 31.3, 30.1, 22.7; FT-IR (neat, cm⁻¹) ν 3348,

1677, 1519, 1483. Anal. Calcd for C₂₈H₃₆N₂O (416.60 g/mol): C, 80.73;

H, 8.71; N, 6.72. Found: C, 80.66; H, 8.68; N 6.69.

4H), 3.71 (s, 6H), 1.29 (s, 9H).¹³C NMR (400 MHz, CDCl₃, ppm) δ

168.3, 166.9, 152.5, 147.9, 140.7, 138.2, 137.2, 136.0, 135.4, 134.0, 133.6,

130.1, 130.0, 128.4, 127.8, 127.3, 127.2, 125.7, 121.9, 121.5, 116.7, 51.9,

39.5, 34.8, 31.2; FT-IR (neat, cm⁻¹) ν 3328, 1673, 1520, 1484. Anal.

Calcd for C₃₈H₃₆N₂O₅(600.70 g/mol): C, 75.98; H, 6.04; N, 4.66.

Found: C, 75.86; H, 6.08; N 4.67.

4-tert-Butyl-2,6-diphenethyl-N-(quinolin-8-yl)benzamide (Table

5, Entry 9). Pd(OAc)₂(8.3 mg, 0.037 mmol), 4-tert-butyl-N-

(quinolin-8-yl)benzamide (225 mg, 0.74 mmol), K₂CO₃(256 mg,

1.85 mmol), pivalic acid (14.8 mg, 0.15 mmol), and (2−iodoethyl)-

benzene (515 mg, 2.22 mmol) were dissolved in tert-amyl alcohol (0.7

mL). The resulting mixture was stirred at 110 °C for 20 h. After column

chromatography (toluene/ethyl acetate 50/1), 350 mg (92%) of

crystalline material was obtained: R_f= 0.30 (toluene/ethyl acetate 50/

1); mp = 160−161 °C (hexanes); ¹H NMR (500 MHz, CDCl₃, ppm) δ

9.98 (s, 1H), 9.04 (dd, J = 7.6, 1.0 Hz, 1H), 8.72 (dd, J = 4.1, 1.7, Hz,

1H), 8.18 (dd, J = 8.4, 1.4 Hz, 1H), 7.66−7.57 (m, 2H), 7.45−7.41 (m,

1H), 7.17−7.13 (m, 4H), 7.10−7.06 (m, 6H), 7.03 (s, 2H), 3.05−2.98

(m, 8H), 1.25 (s, 9H); ¹³C NMR (400 MHz, CDCl₃, ppm) δ 169.0,

151.8, 148.3, 141.8, 138.5, 138.0, 136.4, 135.0, 134.5, 128.6, 128.3, 128.1,

127.5, 125.8, 124.7, 122.0, 121.7, 116.9, 38.3, 36.3, 34.6, 31.3; FT-IR

(neat, cm⁻¹) ν 3350, 1670, 1519, 1484. Anal. Calcd for C₃₆H₃₆N₂O

(512.68 g/mol): C, 84.34; H, 7.08; N, 5.46. Found: C, 84.35; H, 7.10; N

5.56.

Diethyl 7,7′-(5-(tert-Butyl)-2-(quinolin-8-ylcarbamoyl)-1,3-

phenylene)diheptanoate (Table 5, Entry 10). Pd(OAc)₂(8.3 mg,

0.037 mmol), 4-tert-butyl-N-(quinolin-8-yl)benzamide (225 mg, 0.74

mmol), K₂CO₃(256 mg, 1.85 mmol), pivalic acid (14.8 mg, 0.15 mmol),

and ethyl 7-iodoheptanoate (630 mg, 2.22 mmol) were dissolved in tert-

amyl alcohol (1.0 mL). The resulting mixture was stirred at 110 °C for

20 h. After column chromatography (toluene/ethyl acetate 40/1 to 200/

1), 353 mg (77%) of a yellow oil was obtained: TLC R_f= 0.08 (toluene/

ethyl acetate 40/1); ¹H NMR (500 MHz, CDCl₃, ppm) δ 9.90 (s, 1H),

8.97 (dd, J = 7.5, 1.4 Hz, 1H), 8.72 (dd, J = 4.4, 1.6 Hz, 1H), 8.17 (dd, J =

8.3, 1.7 Hz, 1H), 7.63−7.54 (m, 2H), 7.47−7.43 (m, 1H), 7.14 (s, 2H),

4.11− 4.04 (m, 4H), 2.72−2.66 (m, 4H), 2.16−2.10 (m, 4H), 1.73−1.64

(m, 4H), 1.53−1.45 (m, 4H), 1.35 (s, 9H), 1.33−1.18 (m, 14H); ¹³C

NMR (400 MHz, CDCl₃, ppm) δ 173.8, 169.2, 151.9, 148.3, 139.0,

138.5, 136.3, 134.8, 134.5, 128.1, 127.5, 123.9, 121.8, 121.7, 116.7, 60.1,

34.7, 34.2, 33.8, 31.7, 31.4, 29.3, 28.9, 24.8, 14.3; FT-IR (neat, cm⁻¹) ν

3344, 1734, 1519, 1482. Anal. Calcd for C₃₈H₅₂N₂O₅(616.83 g/mol):

C, 73.99; H, 8.50; N, 4.54. Found: C, 73.75; H, 8.61; N, 4.43.

4-(tert-Butyl)-N-(quinolin-8-yl)-2,6-bis(4-(triﬂuoromethoxy)-

benzyl)benzamide (Table 5, Entry 13). Pd(OAc)₂(8.3 mg, 0.037

mmol), 4-tert-butyl-N-(quinolin-8-yl)benzamide (225 mg, 0.74 mmol),

K₂CO₃(256 mg, 1.85 mmol), pivalic acid (14.8 mg, 0.15 mmol), and 1-

(bromomethyl)-4-(triﬂuoromethoxy)benzene (566 mg, 2.22 mmol)

were dissolved in 1.0 mL of tert-amyl alcohol. The resulting mixture was

stirred at 110 °C for 20 h. After column chromatography (toluene/ethyl

acetate 25/1), 433 mg (90%) of a crystalline material was obtained: R_f=

1

0.27 (toluene/ethyl acetate 70/1); mp = 118−119 °C (hexanes); H

NMR (500 MHz, CDCl₃, ppm) δ 9.52 (s, 1H), 8.86 (dd, J = 7.1, 1.9 Hz,

1H), 8.50 (dd, J = 4.3, 1.8 Hz, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 7.60−

7.51 (m, 2H), 7.42−7.37 (m, 1H), 7.19−7.11 (m, 6H), 6.92−6.86 (m,

4H), 4.08 (s, 4H), 1.30 (s, 9H); FT-IR (neat, cm^‑1) ν 3335, 1670, 1523,

1485; ¹³C NMR (400 MHz, CDCl₃, ppm) δ 168.3, 152.6, 148.1, 147.5,

139.2, 138.1, 137.2, 136.2, 135.4, 134.0, 130.1, 127.9, 127.3, 125.7, 122.2,

121.7, 120.8, 120.4 (q, J_C−F= 255.0 Hz), 116.5, 39.0, 34.8, 31.2. ¹⁹F

NMR (376 MHz, CDCl₃, ppm) δ −57.9. Anal. Calcd for C₃₆H₃₀F₆N₂O₃

(652.63 g/mol): C, 66.25; H, 4.63; N, 4.29. Found: C, 66.51; H, 4.58; N

4.33.

4-(tert-Butyl)-2,6-bis(3-nitrobenzyl)-N-(quinolin-8-yl)benzamide

(Table 5, Entry 14). Pd(OAc)₂(8.3 mg, 0.037 mmol), 4-tert-butyl-N-

(quinolin-8-yl)benzamide (225 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85

mmol), pivalic acid (14.8 mg, 0.15 mmol), and 1-(bromomethyl)-3-

nitrobenzene (479 mg, 2.22 mmol) were dissolved in tert-amyl alcohol

(0.7 mL). The resulting mixture was stirred at 110 °C for 20 h. After

column chromatography (toluene/ethyl acetate 40/1 to 30/1), 365 mg

(86%) of a yellow solid was obtained: R_f= 0.31 (toluene/ethyl acetate

1

40/1); mp = 122−123 °C (hexanes); H NMR (400 MHz, CDCl₃,

ppm) δ 9.39 (s, 1H), 8.76 (q, J = 5.6 Hz, 1H), 8.44 (q, J = 4.2 Hz, 1H),

8.13 (q, J = 8.4 Hz, 1H), 7.97− 7.94 (m, 2H), 7.77−7.73 (m, 2H), 7.55−

7.51 (m, 2H), 7.48−7.44 (m, 2H), 7.41−7.37 (m, 1H), 7.26−7.25 (m,

2H), 7.21−7.15 (m, 2H), 4.19 (s, 4H), 1.34 (s, 9H); ¹³C NMR (500

MHz, CDCl₃, ppm) δ 167.8, 153.2, 148.1, 148.1, 142.4, 138.0, 136.5,

136.3, 135.6, 135.2, 133.5, 129.2, 127.8, 127.3, 126.3, 123.7, 122.4, 121.7,

121.2, 116.6, 39.5, 34.9, 31.3; FT-IR (neat, cm⁻¹) ν 3369, 1671, 1517,

1481. Anal. Calcd for C₃₄H₃₀N₄O₅(574.63 g/mol): C, 71.07; H, 5.26;

N, 9.75. Found: C 71.02, H 5.27, N 9.74.

4-(tert-Butyl)-2,6-bis(2-chlorobenzyl)-N-(quinolin-8-yl)benzamide

(Table 5, Entry 11). Pd(OAc)₂(8.3 mg, 0.037 mmol), 4-tert-butyl-N-

(quinolin-8-yl)benzamide (225 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85

mmol), pivalic acid (14.8 mg, 0.15 mmol), and 1-(bromomethyl)-2-

chlorobenzene (456 mg, 2.22 mmol) were dissolved in tert-amyl alcohol

(0.7 mL). The resulting mixture was stirred at 110 °C for 20 h. After

column chromatography (toluene/ethyl acetate 50/1 to 25/1), 286 mg

(70%) of crystalline material was obtained: R_f= 0.38 (toluene/ethyl

4-(tert-Butyl)-2,6-bis(6-(1,3-dioxoisoindolin-2-yl)hexyl)-N-(quino-

lin-8-yl)benzamide (Table 5, Entry 15). Pd(OAc)₂(8.3 mg, 0.037

mmol), 4-tert-butyl-N-(quinolin-8-yl)benzamide (225 mg, 0.74 mmol),

K₂CO₃(256 mg, 1.85 mmol), pivalic acid (14.8 mg, 0.15 mmol), and 2-

(6-iodohexyl)isoindoline-l,3-dione (792 mg, 2.22 mmol) were dissolved

in tert-amyl alcohol (3.0 mL). The resulting mixture was stirred at 110

°C for 40 h. After column chromatography (toluene/ethyl acetate 30/1

to 20/1), 420 mg (74%) of a yellow oil was obtained: R_f= 0.13 (toluene/

ethyl acetate 30/1); ¹H NMR (500 MHz, CDCl₃, ppm) δ 9.88 (s, 1H),

8.96 (dd, J = 7.4, 1.3 Hz, 1H), 8.68 (dd, J = 4.4, 1.6 Hz, 1H), 8.13 (dd, J =

8.4, 1.5 Hz, 1H), 7.82−7.78 (m, 4H), 7.71−7.66 (m, 4H), 7.61−7.51

(m, 2H), 7.39−7.35 (m, 1H), 7.11 (s, 2H), 3.51 (t, J = 7.3 Hz, 4H), 2.63

(t, J = 8.1 Hz, 4H), 1.65 (q, J = 7.8 Hz, 4H), 1.53−1.47 (m, 4H), 1.32 (s,

9H), 1.31−1.19 (m, 8H).¹³C NMR (400 MHz, CDCl₃, ppm) δ 169.2,

168.4, 151.8, 148.2, 138.9, 138.5, 136.3, 134.8, 134.5, 133.8, 132.2, 128.0,

127.5, 124.0, 123.2, 121.8, 121.6, 116.8, 38.0, 34.7, 33.8, 31.8, 31.4, 29.3,

28.5, 26.7; FT-IR (neat, cm⁻¹) ν 3370, 1674, 1519, 1482. Anal. Calcd for

C₄₈H₅₀N₄O₅(762.93 g/mol): C, 75.57; H, 6.61; N, 7.34. Found: C,

75.29; H, 6.74; N 7.27.

4-(tert-Butyl)-2,6-bis(3-methylbut-2-en-1-yl)-N-(quinolin-8-yl)-

benzamide (Table 5, Entry 16). Pd(OAc)₂(8.3 mg, 0.037 mmol), 4-tert-

butyl-N-(quinolin-8-yl)benzamide (225 mg, 0.74 mmol), K₂CO₃(256

mg, 1.85 mmol), pivalic acid (14.8 mg, 0.15 mmol), and 1-bromo-3-

methylbut-2-ene (330 mg, 2.22 mmol) were dissolved in tert-amyl

alcohol (1.0 mL). The resulting mixture was stirred at 110 °C for 96 h.

After column chromatography (hexanes/ethyl acetate 15/1), 72 mg

(22%) of yellow oil was obtained: R_f= 0.31 (hexanes/ethyl acetate 15/

1

acetate 50/1); mp = 140−141 °C (hexanes); H NMR (500 MHz,

CDCl₃, ppm) δ 9.86 (s, 1H), 8.91 (dd, J = 7.3, 1.7 Hz, 1H), 8.61 (dd, J =

4.3, 1.6 Hz, 1H), 8.14 (dd, J = 8.3, 1.8 Hz, 1H), 7.59−7.50 (m, 2H),

7.42−7.37 (m, 1H), 7.24−7.17 (m, 4H), 7.12− 6.99 (m, 6H), 4.25 (s,

4H), 1.20 (s, 9H); ¹³C NMR (400 MHz, CDCl₃, ppm) δ 168.4, 152.3,

148.0, 138.5, 138.2, 136.2, 136.1, 135.6, 134.3, 134.2, 131.4, 129.3, 127.9,

127.6, 127.4, 126.8, 125.3, 121.9, 121.5, 116.8, 36.8, 34.7, 31.1; FT-IR

(neat, cm⁻¹) ν 3341, 1670, 1524, 1486. Anal. Calcd for C₃₄H₃₀Cl₂N₂O

(553.52 g/mol): C, 73.78; H, 5.46; N, 5.06;. Found: C, 73.58; H, 5.57; N

5.05.

Dimethyl 3,3′-((5-(tert-Butyl)-2-(quinolin-8-ylcarbamoyl)-1,3-

phenylene)bis(methylene))dibenzoate (Table 5, Entry 12). Pd(OAc)₂

(8.3 mg, 0.037 mmol), 4-tert-butyl-N-(quinolin-8-yl)benzamide (225

mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol), pivalic acid (14.8 mg,

0.15 mmol), and methyl 3-(bromomethyl)benzoate (508 mg, 2.22

mmol) were dissolved in tert-amyl alcohol (1.0 mL). The resulting

mixture was stirred at 110 °C for 20 h. After column chromatography

(toluene/ethyl acetate 25/1 to 15/1), 318 mg (94%) of crystalline

material was obtained: R_f= 0.18 (toluene/ethyl acetate 25/1); mp =

110−112 °C (hexanes); ¹H NMR (500 MHz, CDCl₃, ppm) δ 9.43 (s,

1H), 8.87 (dd, J = 7.4, 1.6 Hz, 1H), 8.44 (dd,, J = 4.5, 1.7 Hz, 1H), 8.12

(dd, J = 8.2, 1.5 Hz, 1H), 7.78 (s, 2H), 7.63−7.60 (m, 2H), 7.58−7.50

(m, 2H), 7.39−7.32 (m, 3H), 7.18 (s, 2H), 7.16−7.11 (m, 2H), 4.13 (s,

W

dx.doi.org/10.1021/jo4013628 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1); ¹H NMR (500 MHz, CDCl₃, ppm) δ 9.89 (s, 1H), 9.02−8.98 (m,

1H), 8.73−8.69 (m, 1H), 8.19−8.14 (m, 1H), 7.61−7.52 (m, 2H),

7.45−7.43 (m, 1H), 7.15 (s, 2H), 5.33−5.27 (m, 2H), 3.45 (d, J = 6.9

Hz, 4H), 1.50 (s, 6H), 1.46 (s, 6H), 1.34 (s, 9H); ¹³C NMR (400 MHz,

CDCl₃, ppm) δ 169.1, 152.2, 148.1, 138.5, 138.2, 136.3, 134.9, 134.8,

132.4, 127.9, 127.5, 124.2, 123.3, 121.7, 121.6, 116.7, 34.7, 32.6, 31.3,

25.6, 17.8; FT-IR (neat, cm⁻¹) ν 3339, 1675, 1520, 1482; HRMS (m/z)

[M⁺] calcd for C₃₀H₃₆N₂O 440.2828, found 440.2827, error = 0.2 ppm.

General Procedure for Alkylation of 8-Aminoquinoline Amide sp³

C−H Bonds. A 2-dram screw-cap vial was charged with Pd(OAc)₂(5

mol %), K₂CO₃(3 equiv), substrate, pivalic acid (2 equiv), and alkyl

bromide or iodide (4 equiv). tert-Amyl alcohol solvent (0.5−1.0 mL)

was added, and the resulting mixture was stirred and heated at 110 °C for

12−96 h. The conversion was monitored by TLC. After completion of

reaction, ethyl acetate was added to reaction mixture followed by

extraction with water. The aqueous layer was washed with ethyl acetate

(3 × 5 mL). Combined organic extracts were dried over MgSO₄.

Filtration and evaporation under reduced pressure followed by

puriﬁcation by ﬂash chromatography gave pure product.

6-Methyl-N-(quinolin-8-yl)hept-5-enamide (Table 6, Entry 5).

Pd(OAc)₂(8.3 mg, 0.037 mmol), N-(quinolin-8-yl)propionamide

(148 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol), pivalic acid (151

mg, 1.48 mmol), and 1-bromo-3-methylbut-2-ene (441 mg, 2.96 mmol)

were dissolved in tert-amyl alcohol (0.5 mL). The resulting mixture was

stirred at 110 °C for 24 h. After column chromatography (toluene/ethyl

acetate 25/1) 58 mg (29%) of yellow oil was obtained: R_f= 0.43

(toluene/ethyl acetate 25/1); ¹H NMR (500 MHz, CDCl₃, ppm) δ 9.79

(s, 1H), 8.76−8.81 (m, 2H), 8.15 (dd, J = 8.3, 1.7 Hz, 1H), 7.42−7.55

(m, 3H), 5.12−5.19 (m, 1H), 2.55 (t, J = 7.6 Hz, 2H), 2.09−2.16 (m,

2H), 1.81−1.91 (m, 2H), 1.69 (d, J = 0.9 Hz, 3H), 1.59 (s, 3H); ¹³C

NMR (400 MHz, CDCl₃, ppm) δ 172.1, 148.3, 138.5, 136.5, 134.7,

132.8, 128.1, 127.6, 123.8, 121.7, 121.5, 116.6, 37.8, 27.6, 25.9, 25.9,

17.9; FT-IR (neat, cm⁻¹) ν 3357, 1687, 1524, 1486; HRMS electrospray

(m/z) [M⁺+ Na] calcd for C₁₇H₂₀N_2O291.14734, found 291.14693,

error = 0.48 ppm.

5-Methyl-N-(quinolin-8-yl)hexanamide (Table 6, Entry 6). Pd-

(OAc)₂(8.3 mg, 0.037 mmol), N-(quinolin-8-yl)propionamide (148

mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol), pivalic acid (151 mg,

1.48 mmol), and l-iodo-2-methylpropane (544 mg, 2.96 mmol) were

dissolved in tert-amyl alcohol (0.5 mL). The resulting mixture was

stirred at 110 °C for 24 h. After column chromatography (toluene/ethyl

acetate 10/1), 133 mg (78%) of yellow oil was obtained: R_f= 0.45

(toluene/ethyl acetate 10/1); ¹H NMR (500 MHz, CDCl₃, ppm) δ 9.81

(s, 1H), 8.83−8.76 (m, 2H), 8.14 (dd, J = 8.2, 1.6 Hz, 1H), 7.56−7.41

(m, 3H), 2.55 (t, J = 7.6 Hz, 2H), 1.87−1.77 (m, 2H), 1.56 (m, 2H), 1.68

(m, 1H), 1.36−1.27 (m, 2H), 0.94−0.88 (d, J = 6.6 Hz, 6H). This

compound is known.^4b

N-(Quinolin-8-yl)pentanamide (Table 6, Entry 1). Pd(OAc)₂(8.3

mg, 0.037 mmol), N-(quinolin-8-yl)propionamide (148 mg, 0.74

mmol), K₂CO₃(256 mg, 1.85 mmol), pivalic acid (151 mg, 1.48

mmol), and iodoethane (461 mg, 2.96 mmol) were dissolved in tert-

amyl alcohol (0.5 mL). The resulting mixture was stirred at 110 °C for

24 h. After column chromatography (toluene/ethyl acetate 20/1), 133

mg (78%) of a yellow oil was obtained: R_f= 0.20 (toluene/ethyl acetate

1

20/1); H NMR (500 MHz, CDCl₃, ppm) δ 9.80 (s, 1H), 8.77−8.82

(m, 2H), 8.13 (dd, J = 8.4, 1.6 Hz, 1H), 7.41−7.55 (m, 3H), 2.56 (t, 7.5

Hz, 2H), 1.76−1.85 (m, 2H), 1.41−1.51 (m, 2H), 0.97 (t, J = 7.4 Hz,

2H); ¹³C NMR (400 MHz, CDCl₃, ppm) δ 172.1, 148.2, 138.4, 136.5,

134.7, 128.0, 127.5, 121.7, 121.4, 116.5, 38.1, 27.9, 22.6, 14.0; FT-IR

(neat, cm⁻¹) ν 3355, 1688, 1524, 1486. This compound is known.²⁰

N-(Quinolin-8-yl)heptanamide (Table 6, Entry 2). Pd(OAc)₂(8.3

mg, 0.037 mmol), N-(quinolin-8-yl)propionamide (148 mg, 0.74

mmol), K₂CO₃(256 mg, 1.85 mmol), pivalic acid (151 mg, 1.48

mmol), and 1-iodobutane (544 mg, 2.96 mmol) were dissolved in tert-

amyl alcohol (0.6 mL). The resulting mixture was stirred at 110 °C for

24 h. After column chromatography (toluene/ethyl acetate 20/1), 101

mg (53%) of yellow oil was obtained: R_f= 0.56 (toluene/ethyl acetate

4-(2-Bromophenyl)-N-(quinolin-8-yl)butanamide (Table 6, Entry

7). Pd(OAc)₂(8.3 mg, 0.037 mmol), N-(quinolin-8-yl)propionamide

(148 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol), pivalic acid (151

mg, 1.48 mmol), and 1-bromo-2-(bromomethyl)benzene (739 mg, 2.96

mmol) were dissolved in tert-amyl alcohol (0.5 mL). The resulting

mixture was stirred at 110 °C for 24 h. After column chromatography

(toluene/ethyl acetate 15/1), 166 mg (60%) of yellow oil was obtained:

1

R_f= 0.41 (toluene/ethyl acetate 15/1); H NMR (400 MHz, CDCl₃,

ppm) δ 9.81 (s, 1H), 8.82−8.76 (m, 2H), 8.14 (dd, J = 8.2, 1.8 Hz, 1H),

7.55−7.40 (m, 4H), 7.30−7.20 (m, 2H), 7.08−7.02 (m, 1H), 2.87 (t, J =

7.7 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 2.20−2.11 (m, Hz, 2H); ¹³C NMR

(400 MHz, CDCl₃, ppm) δ 171.4, 148.3, 140.9, 138.4, 136.5, 134.6,

132.9, 130.7, 128.0, 127.9, 127.6, 127.5, 124.6, 121.7, 121.5, 116.6, 37.4,

35.5, 25.6; FT-IR (neat, cm⁻¹) ν 3344, 1688, 1524, 1486; HRMS

electrospray (m/z) [M⁺+ Na] calcd for C₁₉H₁₇BrN₂O 391.04221,

found 391.04175, error = 0.27 ppm.

2-Ethyl-N-(quinolin-8-yl)undecanamide (Table 6, Entry 8). Pd-

(OAc)₂(8.3 mg, 0.037 mmol), 2-methyl-N-(quinolin-8-yl)butanamide

(169 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol), pivalic acid (151

mg, 1.48 mmol), and 1-iodooctane (710 mg, 2.96 mmol) were dissolved

in tert-amyl alcohol (0.7 mL). The resulting mixture was stirred at 110

°C for 24 h. After column chromatography (hexanes/ethyl acetate 12/

1), 101 mg (40%) of yellow oil was obtained: TLC R_f= 0.54 (hexanes/

ethyl acetate 12/1); ¹H NMR (400 MHz, CDCl₃, ppm) δ 9.85 (s, 1H),

8.87−8.78 (m, 2H), 8.15 (dd, J = 8.3,1.8 Hz, 1H), 7.56−7.41 (m, 3H),

2.43−2.34 (m, 1H), 1.87−1.74 (m, 2H), 1.69−1.53 (m, 2H), 1.43−1.12

(m, 14H), 1.03−0.96 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.0 Hz, 3H); ¹³C

NMR (400 MHz, CDCl₃, ppm) δ 175.1, 148.3, 138.6, 136.5, 134.7,

128.1, 127.6, 121.7, 121.5, 116.6, 51.2, 33.1, 32.0, 29.9, 29.7, 29.6, 29.4,

27.8, 26.4, 22.8, 14.3, 13.0; FT-IR (neat, cm⁻¹) ν 3356, 2926, 2854,

1689, 1524, 1486, 1324; HRMS electrospray (m/z) [M⁺+ Na] calcd for

C₂₄H₁₉FN₂O 393.13792, found 393.13782, error = 1.16 ppm.

2-(2-Fluoro[1,1′-biphenyl]-4-yl)-N-(quinolin-8-yl)undecanamide

(Table 6, Entry 9). Pd(OAc)₂(8.3 mg, 0.037 mmol), 2-(2-ﬂuoro-[1,1′-

biphenyl]-4-yl)-N-(quinolin-8-yl)propanamide (274 mg, 0.74 mmol),

K₂CO₃(256 mg, 1.85 mmol), pivalic acid (151 mg, 1.48 mmol), and 1-

iodooctane (710 mg, 2.96 mmol) were dissolved in tert-amyl alcohol

(0.7 mL). The resulting mixture was stirred at 110 °C for 24 h. After

column chromatography (hexanes/ethyl acetate 7/1), 162 mg (45%) of

yellow oil was obtained: R_f= 0.29 (hexanes/ethyl acetate 7/1); ¹H NMR

(500 MHz, CDCl₃, ppm) δ 9.98 (s, 1H), 8.81−8.74 (m, 2H), 8.13 (dd, J

= 8.3, 1.8 Hz, 1H), 7.56−7.29 (m, 11H), 3.77−3.70 (t, J = 7.6 Hz, 1H),

1

20/1); H NMR (500 MHz, CDCl₃, ppm) δ 9.80 (s, 1H), 8.79−8.77

(m, 2H), 8.13 (dd, J = 8.2, 1.8 Hz, 1H), 7.53−7.41 (m, 3H), 2.54 (t, J =

7.3 Hz, 2H), 1.84−1.77 (m, 2H), 1.44−1.41 (m, 2H), 1.35−1.31 (m,

4H), 0.91−0.87 (m, 3H). This compound is known.²¹

N-(Quinolin-8-yl)undecanamide (Table 6, Entry 3). Pd(OAc)₂(8.3

mg, 0.037 mmol), N-(quinolin-8-yl)propionamide (148 mg, 0.74

mmol), K₂CO₃(256 mg, 1.85 mmol), pivalic acid (151 mg, 1.48

mmol), and 1-iodooctane (710 mg, 2.96 mmol) were dissolved in tert-

amyl alcohol (0.5 mL). The resulting mixture was stirred at 110 °C for

24 h. After column chromatography (toluene/ethyl acetate 25/1), 126

mg (52%) of yellow oil was obtained: R_f= 0.46 (toluene/ethyl acetate

1

20/1); H NMR (500 MHz, CDCl₃, ppm) δ 9.80 (s, 1H), 8.77−8.82

(m, 2H), 8.13 (dd, J = 8.2, 1.5 Hz, 1H), 7.41−7.55 (m, 3H), 2.52−2.59

(t, J = 7.6 Hz, 2H), 1.82 (q, J = 15.0, 7.6 Hz, 2H), 1.19−1.46 (m, 14H),

0.84−0.91 (m, 3H). This compound is known.^4b

5-Phenyl-N-(quinolin-8-yl)pentanamide (Table 6, Entry 4). Pd-

(OAc)₂(8.3 mg, 0.037 mmol), N-(quinolin-8-yl)propionamide (148

mg, 0.74 mmol), K₂CO₃(256 mg, 1.85 mmol), pivalic acid (151 mg,

1.48 mmol), and (2-iodoethyl)benzene (686 mg, 2.96 mmol) were

dissolved in tert-amyl alcohol (0.5 mL). The resulting mixture was

stirred at 110 °C for 24 h. After column chromatography (toluene/ethyl

acetate 20/1), 138 mg (64%) of yellow oil was obtained: R_f= 0.45

(toluene/ethyl acetate 20/1); ¹H NMR (500 MHz, CDCl₃, ppm) δ 9.72

(s, 1H), 8.75−8.81 (m, 2H), 8.13 (dd, J = 8.3, 1.8 Hz, 1H), 7.40−7.54

(m, 3H), 7.14−7.29 (m, 5H), 2.68 (t, J = 7.5 Hz, 2H), 2.58 (t, J = 7.5 Hz,

2H), 1.82−1.92 (m, 2H), 1.71−1.81 (m, 2H); ¹³C NMR (400 MHz,

CDCl₃, ppm) δ 171.7, 148.2, 142.3, 138.4, 136.5, 134.61, 128.6, 128.4,

128.0, 127.5, 125.9, 121.7, 121.5, 116.5, 38.2, 35.9, 31.2, 25.5; FT-IR

(neat, cm⁻¹) ν 3353, 1687, 1524, 1485; HRMS electrospray (m/z) [M⁺

+ Na] calcd for C₂₀H₂₀N₂O 327.14733, found 327.14703, error = 0.75

ppm.

X

dx.doi.org/10.1021/jo4013628 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

2.37−2.25 (m, 1H), 2.02−1.90 (m, 1H), 1.49−1.15 (m, 14H), 0.89−

0.82 (t, J = 6.8 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃, ppm; list of

signals, C−F coupling not assigned) δ 171.7, 161.2, 158.7, 148.3, 141.6,

141.5, 138.5, 136.4, 135.7, 134.5, 131.1, 131.0, 129.1, 129.0, 128.5, 128.0,

127.9, 127.7, 127.5, 124.2, 124.1, 121.8, 121.7, 116.5, 115.8, 115.6, 54.6,

33.6, 32.0, 29.7, 29.6, 29.4, 27.9, 22.8, 14.2; ¹⁹F NMR (376 MHz, CDCl₃,

ppm) δ −117.3; FT-IR (neat, cm⁻¹) ν 2927, 2854, 1688, 1525, 1484,

1424, 1325; HRMS electrospray (m/z) [M⁺+ Na] calcd for

C₂₄H₁₉FN₂O 393.13792, found 393.13782, error = 1.16 ppm.

75, 6061. (g) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.

(h) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 677. (i) Li, C.-J.

Acc. Chem. Res. 2009, 42, 335. (j) Jazzar, R.; Hitce, J.; Renaudat, A.;

Sofack-Kreutzer, J.; Baudoin, O. Chem.Eur. J. 2010, 16, 2654.

(k) Catellani, M.; Motti, E.; Della Ca, N. Acc. Chem. Res. 2008, 41, 1512.

(l) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed.

2012, 51, 8960. (m) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc.

Rev. 2011, 40, 1885.

(2) (a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.

(b) Messaoudi, S.; Brion, J.-D.; Alami, M. Eur. J. Org. Chem. 2010, 6495.

(c) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269. (d) Engle, K. M.;

Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (e) Guo,

X.; Li, C.-J. Org. Lett. 2011, 13, 4977. (f) Tran, L. D.; Daugulis, O. Org.

Lett. 2010, 12, 4277. (g) Yao, T.; Hirano, K.; Satoh, T.; Miura, M.

Chem.Eur. J. 2010, 16, 12307. (h) Chen, Q.; Ilies, L.; Nakamura, E. J.

Am. Chem. Soc. 2011, 133, 428. (i) Ackermann, L.; Hofmann, N.;

Vicente, R. Org. Lett. 2011, 13, 1875. (j) Ren, P.; Salihu, I.; Scopelliti, R.;

Hu, X. Org. Lett. 2012, 14, 1748. (k) Xiao, B.; Liu, Z.-J.; Liu, L.; Fu, Y. J.

Am. Chem. Soc. 2013, 135, 616. (l) Hofmann, N.; Ackermann, L. J. Am.

Chem. Soc. 2013, 135, 5877. (m) Neufeldt, S. R.; Seigerman, C. K.;

Sanford, M. S. Org. Lett. 2013, 15, 2302. (n) Tauchert, M. E.; Incarvito,

C. D.; Rheingold, A. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.

2012, 134, 1482. (o) Lee, D.-H.; Kwon, K.-H.; Yi, C. S. J. Am. Chem. Soc.

2012, 134, 7325. (p) Tredwell, M. J.; Gulias, M.; Gaunt Bremeyer, N.;

Johansson, C. C. C.; Collins, B. S. L.; Gaunt, M. J. Angew. Chem., Int. Ed.

2011, 50, 1076.

2-Octyl-N-(quinolin-8-yl)cyclohexanecarboxamide (Table 6, Entry

10). Pd(OAc)₂(8.3 mg, 0.037 mmol), N-(quinolin-8-yl)-

cyclohexanecarboxamide (188 mg, 0.74 mmol), K₂CO₃(256 mg, 1.85

mmol), pivalic acid (151 mg, 1.48 mmol), and 1-iodooctane (710 mg,

2.96 mmol) were dissolved in tert-amyl alcohol (0.7 mL). The resulting

mixture was stirred at 110 °C for 24 h. After column chromatography

(hexanes/ethyl acetate 12/1), 42 mg (15%) of yellow oil was obtained:

1

TLC R_f= 0.29 (hexanes/ethyl acetate 12/1); H NMR (500 MHz,

CDCl₃, ppm) δ 9.82 (s, 1H), 8.85−8.79 (m, 2H), 8.16 (dd, J = 8.2, 1.7

Hz, 1H), 7.57−7.43 (m, 3H), 2.22−2.12 (m, 1H), 2.06−1.93 (m, 2H),

1.87−1.05 (m, 20 H), 1.04−0.92 (m, 1H), 0.83−0.78 (t, J = 6.9 Hz, 3H);

¹³C NMR (400 MHz, CDCl₃, ppm) δ 175.2, 148.3, 138.6, 136.5, 134.8,

128.1, 127.6, 121.7, 121.4, 116.6, 54.2, 39.5, 35.0, 32.0, 31.3, 31.1, 30.0,

29.7, 29.4, 26.7, 26.1, 26.0, 22.8, 14.3; FT-IR (neat, cm⁻¹) ν 3354, 2924,

2855, 1685, 1523, 1485, 1327, 1160; HRMS electrospray (m/z) [M⁺+

Na] calcd for C₂₄H₃₄N₂O 389.25689, found 389.25660, error = 0.69

ppm.

Cleavage of the 8-Aminoquinoline Auxiliary: 5-Phenylpentanoic

Acid. 5-Phenyl-N-(quinolin-8-yl)pentanamide (1.0 mmol, 304 mg),

NaOH (2.5 mmol, 100 mg), and ethanol (2.0 mL) were mixed in a 2-

dram vial. The vial was capped, heated, and stirred at 70 °C for 3 h. After

the reaction was complete, the contents of the vial was transferred to

ﬂask and water (10 mL) was added to the reaction mixture. The mixture

was acidiﬁed with HCl (20% aqueous solution) to pH = 1. The product

was extracted with ethyl acetate (5 × 5 mL). The organic layers were

combined, concentrated and subjected to column chromatography in

hexanes/ethyl acetate 80/20. After concentration of the fractions

containing the product, the residue was dried under reduced pressure.

Product was obtained as tan crystals (155 mg, 87% yield): R_f= 0.30

(hexanes/ethyl acetate 80/20); this compound is known;²²¹H NMR

(400 MHz, CDCl₃, ppm) δ 11.82 (br s, 1H)7.33−7.14 (m, 5H), 2.52−

2.40 (t, J = 7.0 Hz, 2H), 2.10−2.04 (t, J = 5.5 Hz, 2H), 1.85−1.54 (m,

4H).

(3) (a) Dyker, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 103. (b) Barder,

T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.

2005, 127, 4685. (c) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.;

Peglion, J.-L.; Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 130, 15157.

(d) Chaumontet, M.; Piccardi, R.; Baudoin, O. Angew. Chem., Int. Ed.

2009, 48, 179. (e) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem.

́

Soc. 2007, 129, 14570. (f) Liegault, B.; Fagnou, K. Organometallics 2008,

27, 4841. (g) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.;

Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (h) Wang,

D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190.

(i) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 1759.

(j) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128,

12634. (k) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,

9886. (l) Wasa, M.; Chan, K. S. L.; Zhang, X.-G.; He, J.; Miura, M.; Yu, J.-

Q. J. Am. Chem. Soc. 2012, 134, 18570. (m) Stowers, K. J.; Fortner, K. C.;

Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 6541. (n) Rodríguez, N.;

̀

́ ́

dez-Ibanez, M. A.; Carretero, J. C. Chem.

̃

Romero-Revilla, J. A.; Fernan

Sci. 2013, 4, 175. (o) Baudoin, O.; Herrbach, A.; Guer

ASSOCIATED CONTENT

* Supporting Information

Spectral data. This material is available free of charge via the

Internet at http://pubs.acs.org.

■

́

itte, F. Angew.

S

Chem., Int. Ed. 2003, 42, 5736. (p) Renaudat, A.; Ludivine, J.-G.;

Rodolphe, J.; Kefalidis, C. E; Clot, E.; Baudoin, O. Angew. Chem., Int. Ed.

2010, 49, 7261. (q) Leskinen, M. V.; Yip, K.-T.; Valkonen, A.; Pihko, P.

M. J. Am. Chem. Soc. 2012, 134, 5750.

AUTHOR INFORMATION

Corresponding Author

*E-mail: olafs@uh.edu.

(4) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.

2005, 127, 13154. (b) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.

2010, 132, 3965. (c) Tran, L. D.; Daugulis, O. Angew. Chem., Int. Ed.

2012, 51, 5188. (d) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012,

134, 7. (e) Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc. 2012,

134, 18237. (f) Tran, L. D.; Roane, J.; Daugulis, O. Angew. Chem., Int. Ed.

2013, 52, 6043. (g) Truong, T.; Klimovica, K.; Daugulis, O. J. Am. Chem.

Soc. 2013, 135, 9342.

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Notes

The authors declare no competing ﬁnancial interest.

^†Deceased.

(5) (a) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8,

3391. (b) Feng, Y.; Chen, G. Angew. Chem., Int. Ed. 2010, 49, 958. (c) Li,

B. T. Y.; White, J. M.; Hutton, C. A. Aust. J. Chem. 2010, 63, 438.

(d) Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 19076.

(e) Gutekunst, W. R.; Gianatassio, R.; Baran, P. S. Angew. Chem., Int. Ed.

2012, 51, 7507. (f) Feng, Y.; Wang, Y.; Landgraf, B.; Liu, S.; Chen, G.

Org. Lett. 2010, 12, 3414. (g) Zhao, Y.; Chen, G. Org. Lett. 2011, 13,

4850. (h) Zhao, Y.; He, G.; Nack, W. A.; Chen, G. Org. Lett. 2012, 14,

2948. (i) Ano, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2012, 14, 354.

(j) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984.

(k) Huang, L.; Li, Q.; Wang, C.; Qi, C. J. Org. Chem. 2013, 78, 3030.

(l) Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am.

Chem. Soc. 2013, 135, 2124. (m) He, G.; Chen, G. Angew. Chem., Int. Ed.

ACKNOWLEDGMENTS

■

This research was supported by the Welch Foundation (Grant

No. E-1571), NIGMS (Grant R01GM077635), and Camille and

Henry Dreyfus Foundation.

REFERENCES

■

(1) Reviews: (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.

2010, 110, 624. (b) Ackermann, L. Chem. Rev. 2011, 111, 1315.

(c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.

2009, 48, 5094. (d) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem.

Res. 2009, 42, 1074. (e) Alberico, D.; Scott, M. E.; Lautens, M. Chem.

Rev. 2007, 107, 174. (f) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010,

Y

dx.doi.org/10.1021/jo4013628 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

2011, 50, 5192. (n) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J.

Am. Chem. Soc. 2013, 135, 6030. (o) Rouquet, G.; Chatani, N. Chem. Sci.

2013, 4, 2201. (p) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2013, 135,

5308. (q) Nishino, M.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem.,

Int. Ed. 2013, 52, 4457. (r) Suess, A. M.; Ertem, M. Z.; Cramer, C. J.;

Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 9797. (s) Aihara, Y.; Chatani, N.

Chem. Sci. 2013, 4, 664.

(6) (a) Canty, A. J. Acc. Chem. Res. 1992, 25, 83. (b) Racowski, J. M.;

Dick, A. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 10974.

(c) Sobanov, A. A.; Vedernikov, A. N.; Dyker, G.; Solomonov, B. N.

Mendeleev Commun. 2002, 1, 14. (d) Amatore, C.; Catellani, M.;

Deledda, S.; Jutand, A.; Motti, E. Organometallics 2008, 27, 4549.

(e) Guo, R.; Portscheller, J. L.; Day, V. W.; Malinakova, H. C.

Organometallics 2007, 26, 3874. (f) Powers, D. C.; Geibel, M. A. L.;

Klein, J. E. M. N.; Ritter, T. J. Am. Chem. Soc. 2009, 131, 17050.

(g) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234.

(7) Ittel, S. D.; Johnson, L. K.; Brookhart, M. Chem. Rev. 2000, 100,

1169.

(8) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211.

(9) Bon, E.; Bigg, D. C. H.; Bertrand, G. J. Org. Chem. 1994, 59, 4035.

(10) Shabashov, D.; Daugulis, O. J. Org. Chem. 2007, 72, 7720.

(11) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans.

1915, 107, 1080.

(12) Marsh, C. C.; Schuna, A. A.; Sundstrom, W. R. Pharmacotherapy

1986, 6, 10.

(13) Shinji, C.; Maeda, S.; Imai, K.; Yoshida, M.; Hashimoto, Y.;

Miyachi, H. Bioorg. Med. Chem. 2006, 14, 7625.

(14) Setsuo, F.; Kato, K.; Mukaiyama, T. Chem. Lett. 2008, 37, 506.

(15) Yu, H.; Ballard, C. E.; Wang, B. Tetrahedron Lett. 2001, 42, 1835.

(16) Nag, S.; Butcher, R. J.; Bhattacharya, S. Eur. J. Inorg. Chem. 2007,

1251.

(17) Arvapalli, V. S.; Chen, G.; Kosarev, S.; Tan, M. E.; Xie, D.; Yet, L.

Tetrahedron Lett. 2010, 51, 284.

(18) Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.;

Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 6061.

̈

(19) Gurbuz, N.; Ozdemir, I.; Çetinkaya, B. Tetrahedron Lett. 2005, 46,

̈

2273.

(20) Lee, J. C., Jr.; Peris, E.; Rheingold, A. L.; Crabtree, R. H. J. Am.

Chem. Soc. 1994, 116, 11014.

(21) Heuer, H. W.; Wehrmann, R.; Elschner, A., Elektrolumineszier-

ende Anordnungen unter Verwendung von Bor-Chelaten von 8-

Aminochinolin-Derivaten. DE 19829949 A1, May 1, 2000.

(22) Klemm, L. H.; Bower, G. M. J. Org. Chem. 1958, 23, 344.

Z

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Scope and limitations of auxiliary-assisted, palladium-catalyzed arylation and alkylation of sp2 and sp3 C-H bonds

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