Pd(OAc)2/AgOAc catalytic system based bidentate ligand directed regiocontrolled C-H arylation and alkylation of the C-3 position of thiophene- and furan-2-carboxamides

FULL PAPER

DOI: 10.1002/ejoc.201500249

Pd(OAc)₂/AgOAc Catalytic System Based Bidentate Ligand Directed

Regiocontrolled C–H Arylation and Alkylation of the C-3 Position of

Thiophene- and Furan-2-carboxamides

Rayavarapu Padmavathi,^[a]Rathinam Sankar,^[a]Bojan Gopalakrishnan,^[a]

Ramarao Parella,^[a]and Srinivasarao Arulananda Babu*^[a]

Keywords: Synthetic methods / Arylation / C–H activation / Palladium / Regioselectivity

A contemporary method is reported for the Pd(OAc)₂/AgOAc

good to very good yields. The bidentate ligand directed

catalytic system based bidentate ligand directed, regioselec- Pd(OAc)₂/AgOAc based strategy was also successfully em-

tive C–H activation and C–C bond formation at the C-3 posi-

tion of thiophene- and furan-2-carboxamides, which are de-

rived from 8-aminoquinoline or 2-(methylthio)aniline. The

Pd-catalyzed C–H arylation of thiophene- and furan-2-

carboxamides with a variety of aryl iodides and heteroaryl

iodides was highly regioselective and afforded C-3-arylated

thiophene-2-carboxamides and furan-2-carboxamides in

ployed for benzylation and alkylation reactions of the thio-

phene-2-carboxamides. These reactions occurred with high

regioselectivity to afford the C-3-benzylated and C-3-alkyl-

ated thiophene-2-carboxamides in good yields. The observed

regioselectivity of these reactions was confirmed by X-ray

crystal structure analyses of compounds 3e, 5a, and 6a.

The Pd-catalyzed synthesis of heterobiaryls, especially

thiophenes and furans that are connected to an aryl (het-

eroaryl) moiety, has been widely successful through the di-

rect C–H arylation of thiophenes and furans with aryl hal-

ides (Scheme 1).^[5,13,14]However, a survey of the literature

shows that only a few reports provide specific reaction con-

ditions for selective arylation at the less reactive C-3 and C-

4 positions of thiophenes and furans. In addition, there are

Introduction

Arylated heteroarenes (heterobiaryls) are frequently

found in natural products and biologically active medici-

nally important molecules and used for the preparation of

organic materials.^[1–3]Given the significance of heterobiar-

yls, the development of effective methods to construct het-

erobiaryl motifs is considered an essential topic of chemical

synthesis. Generally, well-established transition-metal-cata-

lyzed cross-coupling reactions (e.g., Suzuki, Negishi, and

Stille reactions) have been used to assemble heterobiaryl

motifs.^[4]However, with regard to traditional cross-coupling

strategies, there are some drawbacks such as the need for

prior preparation of the organometallic reagents and the

functionalization of one or both of the coupling partners

as well as the production of stoichiometric amounts of met-

allic waste. Many research groups have focused on the di-

rect coupling of heteroaromatics with aryl (heteroaryl) hal-

ides or arenes by using a C–H functionalization strategy

without the need to preactivate one or both of the coupling

partners.^[5–8]Generally, Pd-based catalysts have been used

for the direct coupling of heteroaromatics with aryl (het-

eroaryl) halides or arenes and periodically, Rh-,^[9]Ru-,^[10]

Cu-,^[11]and Ir-based^[12]catalysts have also been used.

[a] Department Chemical Sciences, Indian Institute of Science

Education and Research (IISER) Mohali,

Knowledge City, Sector 81, SAS Nagar, Mohali, Manauli P. O.,

Punjab 140306, India

E-mail: sababu@iisermohali.ac.in

http://ww w .iisermohali.ac.in/html/faculty/babu.html

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201500249.

Scheme 1. Regioselective arylation of thiophene- and furan-2-

carboxamides.

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some shortcomings to this strategy such as: (a) in most of gand directed C-3 arylation of thiophene-2-carboxamide,

the Pd-catalyzed direct C–H arylations of thiophenes and which was derived from 8-aminoquinoline (Daugulis’s li-

furans, the reaction selectively occurs at the more reactive gand),^[25a]by using an aryl borate reagent in the presence

C-2 and C-5 positions,^[5,13–16]which are relatively more re- of Fe(acac)₃(acac = acetylacetonate), (Z)-1,2-bis(diphenyl-

active towards arylation than the C-3 and C-4 positions phosphino)ethene (dppen), ZnBr₂·TMEDA (TMEDA =

(however, there are examples of the addition of an olefin to N,N,NЈ,NЈ-tetramethylethylenediamine), and 2,3-dichloro-

the C-3–H bond of thiophenes and furans);^[6r,6s](b) in some isobutane (DCIB). Notably, in this case, the aryl borate

cases, C–H arylation at the C-3 and C-4 positions of the coupling partner was preprepared from Ph-Bpin (4,4,5,5-

thiophene or furan system has only been achieved by using tetramethyl-2-phenyl-1,3,2-dioxaborolane) and BuLi. Apart

an aryl triflate or aryl boron reagent as one of the coupling from this one example, other cases of the C-3 functionaliza-

partners; (c) arylation at the C-3 or C-4 position of a thio- tion of thiophenes-2-carboxamides do exist that employ

phene or furan system only occurs if other positions (i.e., coupling partners other than aryl halides, triflates, and

C-2 and C-5) are already substituted;^[16,17]and (d) arylation boronic acids.^[27–31]

at multiple positions of thiophene and furan systems only

The above rationale indicates that there are only few re-

ports of regioselective C–H arylation at the C-3 position of

occur under specific experimental conditions.^[18]

With regard to examples of bimolecular Pd-catalyzed se- C-2-substituted thiophene and furan systems by using aryl

lective C–H arylations at the C-3 or C-4 position of thio- halides.^[16c,22]Additionally, apart from the Doucet’s and It-

phenes and furans with aryl triflate or aryl boronic acid ami’s examples^[16c,22]of Pd/phosphine-based C-3 arylations

reagents,^[19–21]Miura’s group^[19]achieved the direct C-3 of thiophene and furan systems, there is no other method

arylation of thiophene-2-carboxylic acid phenylamide by available for the regiocontrolled C-3 arylation of these sys-

using PhOTf (OTf = trifluoromethanesulfonate) in the pres- tems by using aryl or alkyl iodides as the coupling partners.

ence of Pd(OAc)₂and [P(o-biphenyl)(tBu)₂]. In this reac- Furthermore, under the reported conditions for C-3 aryl-

tion, the C-3-arylated product was obtained (71%) along ations, alkylations at the C-3 position of thiophene and

with the diarylated (at C-3 and C-5) product (8%). The It- furan systems have not been explored. In continuation of

ami and Bach groups^[20]demonstrated the C-4 arylation of our interest in bidentate ligand directed Pd(OAc)₂/AgOAc

C-2/C-3-substituted thiophenes by using aryl boronic acids. catalytic system based C–H functionalization reactions, we

In contrast, Studer reported^[21]a 2-pyridyl-directed C-3 investigated the ortho-selective C–H arylation and alkyl-

arylation of a thiophene moiety by using an aryl boronic ation of the C-3 position of thiophene- and furan-2-carbox-

acid in the presence of [RhCl(C₂H₄)₂]₂/P[p-(CF₃)C₆H₄]₃amides, which were derived from bidentate ligands,^[25a]by

and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO).

using aryl and alkyl iodides. To the best of our knowledge,

Regarding a bimolecular Pd-catalyzed C–H arylation at this approach has not been explored. It is significant that

the C-3 or C-4 position of thiophenes and furans with aryl various C-3-arylated thiophene- and furan-2-carboxylic

halides,^[17,22]Itami’s group^[16c]reported the β-selective C-4 acid derivatives are known to exhibit a variety of biological

arylation of C-2/C-3-substituted thiophenes by using activities,^[2,3]and this work focuses on the construction of

iodoarenes in the presence of PdCl₂, P[OCH(CF₃)₂]₃, and several C-3-arylated thiophene- and furan-2-carboxylic acid

Ag₂CO₃. The arylation of unsubstituted thiophene gave C- derivatives. Herein, we report a contemporary method for

3- and C-2-arylated thiophenes in 86% yield and a ratio of a Pd(OAc)₂/AgOAc catalytic system based bidentate ligand

88:12.^[16c]Similarly, Doucet’s group successfully demon- directed,^[25a]highly regiocontrolled C–H arylation as well

strated^[22b,22c]the C-3 arylation of thiophene-2-carboxylic as alkylation of the C-3 position of thiophene- and furan-

acid benzylamide, thiophene-2-carboxylic acid phen- 2-carboxamides, which are derived from 8-aminoquinoline

ylamide, N-benzyl-2-furamide, and N-phenyl-2-furamide by or 2-(methylthio)aniline.

using bromoarenes in the presence of Cs₂CO₃and a cata-

lytic amount of PdCl(C₃H₅)(dppb), which was preprepared

from [Pd(C₃H₅)Cl]₂and 1,4-bis(diphenylphosphino)butane

(dppb). Under similar reaction conditions, thiophene-2-

Results and Discussion

carboxylic acid diethylamide afforded the corresponding C-

To begin our investigation of this Pd(OAc)₂/AgOAc cata-

5-arylated thiophene derivative.^[22b]Apart from these re- lytic system based bidentate ligand-directed C–H arylation

ports, there are also examples of the intramolecular cycliza- method, we first prepared substrate 1a {N-[2-(methylthio)-

tion of thiophene and furan derivatives that involves the C- phenyl]thiophene-2-carboxamide} by linking thiophene-2-

3 position^[23]as well as the C-3 arylation of benzothio- carbonyl chloride with the bidentate ligand 2-(methylthio)-

phenes and benzofurans.^[24]

aniline (Daugulis’s auxiliary).^[25a,25b]We then proceeded to

In recent years, the chelation-assisted/ligand-directed re- optimize the reaction conditions for the Pd-catalyzed C–H

gioselective functionalization of ortho-C–H bonds of carb- arylation of 1a with aryl iodide 2a (5-bromo-2-iodopyrid-

oxylic acid derivatives has become

a powerful ap- ine) as delineated in Table 1. The reaction between N-[2-

proach.^[5–8,25]A wide variety of functional groups and moi- (methylthio)phenyl]thiophene-2-carboxamide (1a) and 5-

eties in organic molecules have been shown to serve as di- bromo-2-iodopyridine (2a) with AgOAc as an additive in

recting groups for the functionalization of C–H bonds. Ilies the absence of a catalyst in toluene at 110 °C for 24 h did

and Nakamura^[26]reported an example of a bidentate li- not give any C–H arylated products (Table 1, Entry 1). On

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Arylation and Alkylation of Thiophene- and Furan-2-carboxamides

Table 1. Optimization reactions of 2-(methylthio)aniline-directed, regiocontrolled C–H arylation of C-3 position of thiophene-2-carbox-

amide 1a.^[a]

[a] All reactions employed substrate 1a (0.25 mmol) and iodo compound 2a (1 mmol).

the other hand, when the reaction was carried out in the dium(II) trifluoroacetate [Pd(TFA)₂], PdCl₂, Pd(PPh₃)₄,

presence of 5 mol-% of the Pd(OAc)₂catalyst without the and Pd(dba)₂(dba = dibenzylideneacetone) instead of

additive in toluene at 110 °C for 24 h, C-3-arylated product Pd(OAc)₂, but there was no significant improvement to the

3a {3-(5-bromopyridin-2-yl)-N-[2-(methylthio)phenyl]thio- yield (27–66%; Table 1, Entries 9–12,). When we carried out

phene-2-carboxamide} was produced in 15% yield (Table 1, the reaction in other solvents such as tert-amyl alcohol,

Entry 2). We then carried out the C–H arylation in the pres- tert-butanol, 1,2-dichloroethane (1,2-DCE), and MeCN,

ence of 5 mol-% of the Pd(OAc)₂catalyst and AgOAc as the yield of C-3-arylated thiophene-2-carboxamide 3a did

the additive in toluene at 110 °C for 24 h. This reaction was not significantly improve (12–54%; Table 1, Entries 13–16).

highly regioselective and provided C-3-arylated product 3a

in 81% yield (Table 1, Entry 3).

Next, we focused our attention on the generality and

scope of this bidentate ligand directed [2-(methylthio)anil-

The Pd-catalyzed ortho-C–H arylation reaction of sub- ine] Pd-catalyzed regioselective direct arylation of substrate

strate 1a with 5-bromo-2-iodopyridine (2a) was then carried 1a. In this regard, we performed the reaction with different

out in the presence of Ag₂CO₃, instead of AgOAc, which aryl iodides such as 1-(4-iodophenyl)ethanone, 6-iodo-2,3-

afforded the C-3-arylated thiophene-2-carboxamide 3a in dihydrobenzo[b][1,4]dioxine, and 1-iodo-2,4-dimethoxy-

low yield (29%) (Table 1, Entry 4). This result indicates that benzene in the presence of 5 mol-% of Pd(OAc)₂and the

AgOAc is acting as an additive, which helps to regenerate additive AgOAc, which afforded the corresponding C-3-ar-

Pd(OAc)₂in the catalytic cycle.^{[7,8,25a,25b]}Further Pd-cata- ylated thiophene-2-carboxamides 3b–3d in 25–68% yield

lyzed ortho-C–H arylation reactions between substrate 1a (Table 2). Product 3d was obtained in only 25% yield, and

and 5-bromo-2-iodopyridine (2a) in the presence of other in this case, the presence of the OMe group at the ortho

additives/bases such as K₂CO₃, Na₂CO₃, potassium acetate, position of 1-iodo-2,4-dimethoxybenzene could have steri-

and potassium tert-butoxide, instead of AgOAc, gave C-3- cally hindered in the C–H arylation process. Subsequently,

arylated thiophene-2-carboxamide 3a in low yields (Table 1, we carried out the arylation reaction of substrate 1a with

Entries 5–8). The arylation reaction was also performed in various heteroaryl iodides. These reactions were also highly

the presence of other palladium catalysts such as palla- regioselective and furnished the corresponding C-3-arylated

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Table 2. Regiocontrolled direct C–H arylation of C-3 position of thiophene- and furan-2-carboxamides 1a and 1b directed by 2-(meth-

ylthio)aniline moiety.^[a]

[a] All reactions employed substrate 1a or 1b (0.25 mmol) and an aryl iodide (1 mmol).

thiophene-2-carboxamides 3e–3g in yields of 49–82%

(Table 2).^[32]In addition, we prepared substrate 1b {N-[2-

(methylthio)phenyl]furan-2-carboxamide} by linking furan-

2-carbonyl chloride with bidentate ligand 2-(methylthio)an-

iline. Then, we performed the C-3–H arylation of substrate

1b by using different aryl iodides such as 1-(4-iodophenyl)-

ethanone, 6-iodo-2,3-dihydrobenzo[b][1,4]dioxine, and 5-

bromo-2-iodopyridine in the presence of 5 mol-% of the

Pd(OAc)₂and AgOAc. Again, these reactions were highly

regioselective and gave the corresponding C-3-arylated

furan carboxamides 4a–4c in 38–40% yield (Table 2).^[32]

When compared to the yields obtained with substrate 1a,

the arylation reactions of 1b gave arylated products 4a–4c

in relatively lower yields.

Table 3. Regiocontrolled direct C–H arylation of the C-3 position

of thiophene-2-carboxamide 1c directed by the 8-aminoquinoline

moiety.^[a]

To examine the capability of a different bidentate ligand

and improve the yield of the direct C–H arylation of the

thiophene-2-carboxamides, we prepared substrate 1c [N-

(quinolin-8-yl)thiophene-2-carboxamide] by linking thio-

phene-2-carbonyl chloride with 8-aminoquinoline (Daugul-

is’s auxiliary), the most utilized bidentate ligand. We then

performed the C–H arylation of 1c with different aryl iod-

ides such as 1-(4-iodophenyl)ethanone and 1-iodo-4-meth-

oxybenzene in the presence of 5 mol-% of Pd(OAc)₂and

AgOAc, which regioselectively afforded C-3-arylated thio-

phene-2-carboxamides 5a and 5b in 70 and 79% yield,

respectively (Table 3). In addition, we carried out the trans-

[a] All reactions employed substrate 1c (0.25 mmol) and an iodo

formation by using substrate 1c and various heteroaryl iod- compound (1 mmol).

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Arylation and Alkylation of Thiophene- and Furan-2-carboxamides

ides. These reaction proceeded with high regioselectively to 1d with various heteroaryl iodides, which also regioselec-

afford the corresponding thiophene carboxamides 5c–5f in tively afforded the corresponding furan-2-carboxamides 6e–

62–73% yield (Table 3). The reactivity of thiophene-2- 6h in 24–60% yield (Table 4).^[32]The reactivity of the furan-

carboxamide 1a [assembled from the bidentate ligand 2- 2-carboxamide 1b [assembled from the bidentate ligand 2-

(methylthio)aniline] was comparable to that of substrate 1c (methylthio)aniline] was almost comparable to that of 1d

(assembled from the bidentate ligand 8-aminoquinoline), (assembled from the bidentate ligand 8-aminoquinoline).

and the yields of C-3-arylated products 5a–5f were also However, the yields of products 6a–6h were slightly higher

comparable to those of products 3a–3h.

than those of 4a–4c. We further prepared benzothiophene-

Hence, we focused on improving the yields of the direct 2-carboxamides 1e and 1f as well as benzofuran-2-carbox-

C–H arylation of the furan-2-carboxamides, as 1b [as- amide 1g by using the bidentate ligands 8-aminoquinoline

sembled from bidentate ligand 2-(methylthio)aniline] af- and 2-(methylthio)aniline. Then, we carried out the C-3–H

forded the corresponding C-3-arylated products 4a–4c in arylation reactions of 1e–1g with different aryl iodides such

poor yields. Accordingly, we prepared substrate 1d [N- as 1-(4-iodophenyl)ethanone, 5-bromo-2-iodopyridine, and

(quinolin-8-yl)furan-2-carboxamide] by linking furan-2- methyl 4-iodobenzoate in the presence of 5 mol-% of

carbonyl chloride with bidentate ligand 8-aminoquinoline. Pd(OAc)₂and AgOAc. As a result, the corresponding C-3-

We then investigated the C–H arylation of substrate 1d with arylated benzothiophene-2-carboxamides 7a–7d were pro-

various aryl iodides such as 1-(4-iodophenyl)ethanone, 1- duced in yields of 16–66% (Scheme 2).

iodo-4-methoxybenzene, methyl 4-iodobenzoate, and 6-

To extend the investigation to the directing groups and

iodo-2,3-dihydrobenzo[b][1,4]dioxine in the presence of study the reactivity patterns of thiophene- and furan-2-

5 mol-% of Pd(OAc)₂and AgOAc. These reactions were carboxamides, which were derived from other bidentate

highly regioselective and gave the corresponding C-3-aryl- auxiliaries, we assembled substrates 8a and 8b by linking

ated furan carboxamides 6a–6d in 34–67% yield (Table 4). thiophene-2-carbonyl chloride with bidentate ligands such

Along this line of reasoning, we carried out the Pd-cata- as N,N-dimethylethane-1,2-diamine and N,N-diethylethane-

lyzed bidentate ligand directed C–H arylation reactions of 1,2-diamine. We then performed the C–H arylation of sub-

strates 8a and 8b by using 2g in the presence of 5 mol-% of

Pd(OAc)₂and the additive AgOAc, but the corresponding

C-3-arylated thiophene-2-carboxamides 9a and 9b were not

Table 4. Regiocontrolled direct C–H arylation of C-3 position of

furan-2-carboxamide 1d directed by 8-aminoquinoline moiety.^[a]

produced (Scheme 3). These results indicate that N,N-di-

methylethane-1,2-diamine and N,N-diethylethane-1,2-di-

amine were not effective bidentate ligands. Under the opti-

mized reaction conditions (Table 1), we further investigated

the C-3 arylation of thiophene- and furan-2-carboxamides

8c and 8d, which were derived from aniline instead of a

bidentate ligand. Accordingly, the direct C–H arylation of

substrates 8c and 8d with different aryl iodides in the pres-

ence of 5 mol-% of Pd(OAc)₂and AgOAc did not provide

the corresponding C-3-arylated thiophene-2-carboxamides

9c–9f (Scheme 3). As a result of the reaction that involved

substrate 8d, we obtained product 10, which was formed by

arylation occurring at the C-5 position of the furan ring.

Altogether, these observations indicate that the reaction

conditions [Pd(OAc)₂/AgOAc catalytic system] employed in

this investigation only work well with thiophene- and furan-

2-carboxamides 1a–1g, which were derived from bidentate

ligands. Furthermore, the results of above investigation are

in concurrence with literature reports, as the role of the bi-

dentate auxiliaries (Daugulis’s auxiliaries) along with the

mechanism of the C–H activation process involving the

Pd(OAc)₂/AgOAc catalytic system has been well-documen-

ted.^{[7,8,25a,25b]}

Finally, we proceeded to expand the usefulness of this C–

H functionalization and direct C–C bond-forming protocol

for the preparation of C-3-alkylated thiophene-2-carboxam-

ides. First, we attempted the direct C–H benzylation of sub-

strate 1c by using 1-(bromomethyl)-4-(trifluoromethyl)-

benzene (11) in the presence of 5 mol-% of Pd(OAc)₂and

the additive AgOAc in toluene at 110 °C for 48 h. As a re-

sult, C-3-benzylated product 12 {N-(quinolin-8-yl)-3-[4-(tri-

[a] All reactions employed substrate 1d (0.25 mmol) and an iodo

compound (1 mmol).

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Scheme 2. Regiocontrolled direct C–H arylation of C-3 position of carboxamides 1e–1g. All reactions were performed by using substrates

1e–1g (0.25 mmol) and an iodo compound (1 mmol).

fluoromethyl)benzyl]thiophene-2-carboxamide} was re-

gioselectively afforded in 70% yield (Scheme 4). Similarly,

the Pd-catalyzed benzylation of substrate 1c with 1-(bromo-

methyl)-4-nitrobenzene (13) afforded C-3-benzylated prod-

uct 14 in 85% yield (Scheme 4). We then performed further

alkylations of the C-3 position of thiophene-2-

carboxamide 1c by using different alkyl iodides (Scheme 4).

In the presence of 5 mol-% of Pd(OAc)₂, K₂CO₃and pivalic

acid in tert-amyl alcohol at 100°°C for 24 h, the corre-

sponding C-3-alkylated products 16a–16d were regioselec-

tively afforded in yields of 45–94% (Scheme 4). The reac-

tion of substrate 1c with ethyl iodoacetate in the presence

of 10 mol-% of Pd(OAc)₂and the additives Ag₂CO₃and

(BnO)₂PO₂H afforded C-3-alkylated product 16e in 43%

yield (Scheme 4). However, the reaction of substrate 1c with

2-iodoacetonitrile in the presence of 10 mol-% of

Pd(OAc)₂and additives Ag₂CO₃and (BnO)₂PO₂H failed to

afford C-3-alkylated product 16f (Scheme 4).

The observed regioselectivity in this directing group en-

abled Pd-catalyzed ortho-arylation of thiophene-2-carbox-

amides and the structures of regioisomers 3, 5, 12, 14, and

16 were ascertained by the coupling constants (J) of the

doublets corresponding to the C-4 and C-5 protons. These

coupling constants were found to be approximately 5 Hz,

as reported in the literature.^[22b]Similarly, the structure of

regioisomers 4 and 6 were also ascertained by the coupling

constants (J) of the doublets from the C-4 and C-5 protons.

This value (J) was approximately 1.8 Hz, as reported in the

literature.^[22b]The coupling constant (J) of the doublets cor-

responding to the C-3 and C-4 protons was also used to

determine the structure of regioisomer 10. In this case, the

coupling constant was 3.6 Hz, as reported in the litera-

Scheme 3. Pd-catalyzed C–H arylation of thiophene- and furan-2-

carboxamides 8a–8d. All reaction were performed by using sub-

strates 8a–8d (0.25 mmol), an iodo compound (1 mmol),

Pd(OAc)₂(5 mol-%), AgOAc (0.55 mmol), and toluene (3 mL) at

110 °C for 24 h.

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Arylation and Alkylation of Thiophene- and Furan-2-carboxamides

Figure 1. X-ray crystal structures (ORTEP diagrams) of com-

pounds 3a, 5a, and 6a.

Conclusions

In summary, we have reported a contemporary and con-

venient method that involves a Pd(OAc)₂/AgOAc catalytic

system based bidentate ligand directed, regioselective C–H

activation/functionalization and C–C bond formation of

the C-3 position of thiophene- and furan-2-carboxamides,

which are derived from the bidentate ligands 8-aminoquin-

oline or 2-(methylthio)aniline. Given the importance of the

C-3-arylated thiophene- and furan-2-carboxamides as bio-

logically active compounds, our method for the Pd(OAc)₂-

catalyzed C-3–H arylation of thiophene- and furan-2-car-

boxamides with a variety of aryl iodides or heteroaryl iod-

ides was highly regioselective and afforded various C-3-

arylated thiophene- and furan-2-carboxamides in good to

very good yields. By using this catalytic system, we have

also assembled various C-3-benzylated- and C-3-alkylated

thiophene- and furan-2-carboxamides in good to very good

yields.

Experimental Section

General Methods: IR spectra were recorded as thin films or KBr

pellets. Melting points are uncorrected. The ¹H and ¹³C NMR

spectroscopic data were recorded with 400 and 100 MHz spectrom-

eters, respectively, and TMS was used as an internal standard. Col-

umn chromatography was carried out on silica gel (100–200 mesh).

Reactions were performed in anhydrous solvents under nitrogen.

Solutions were dried with anhydrous Na₂SO₄. Thin layer

chromatography analyses were performed on silica gel plates, and

the components were visualized with iodine vapor. Isolated yields

were reported for all compounds, and the yields were not opti-

mized. The column chromatographic purification of the crude mix-

ture for all of the reactions gave only the major regioisomer in pure

form. In general, all reactions were monitored by TLC, and the

reactions were quenched upon consumption of the starting mate-

rial (i.e., 1a–1g). In some cases, the reactions were quenched at the

reaction time reported in the corresponding Table/Scheme, as the

starting material was not consumed even after a prolonged period

of time. The compound numbers for the aryl halides used in this

work: 5-Bromo-2-iodopyridine (2a), 1-(4-iodophenyl)ethanone

(2b), 6-iodo-2,3-dihydrobenzo[b][1,4]dioxine (2c), 1-iodo-2,4-dime-

thoxybenzene (2d), 2-chloro-4-iodopyridine (2e), 2-fluoro-5-iodop-

yridine (2f), 2-iodothiophene (2g), 1-iodo-4-methoxybenzene (2h),

2-chloro-5-iodopyridine (2i), methyl 4-iodobenzoate (2j).

Scheme 4. Pd-catalyzed C-3–H benzylation and alkylation of thio-

phene-2-carboxamide 1c. All reactions employed 1c (0.25 mmol)

and benzyl bromide or alkyl iodide (1 mmol). ^[a]The reaction em-

ployed 1c (0.25 mmol) and 15e (0.5 mmol). ^[b]Reagents and condi-

tions: 1c (0.25 mmol), 15e (1 mmol), Pd(OAc)₂(5 mol-%), K₂CO₃

(0.75 mmol), pivalic acid (PivOH, 20 mol-%), tert-amyl-OH

(0.3 mL), 100 °C, 30 h. ^[c]The reaction employed 1c (0.25 mmol)

and 15f (1 mmol). ^[d]Reagents and conditions: 1c (0.25 mmol), 15f

(1 mmol), Pd(OAc)₂(10 mol-%), K₂CO₃(0.75 mmol), PivOH

(40 mol-%), tert-amyl-OH (3 mL), 100 °C, 24 h.

Procedure for Synthesis of Hetereocyclic Carboxamides 1a–1g and

8a–8d: The corresponding carboxylic acid (1.5 mmol) was dissolved

in SOCl₂(4 mmol), and the resulting mixture was stirred at room

temp. for 24 h under nitrogen. After this period of time, the mixture

was concentrated in vacuo, and the residue was dissolved in anhy-

ture.^[22b]The observed regioselectivity of these reactions

along with the structures of the representative regioisomers

3a, 5a, and 6a were further confirmed by X-ray crystal

structure analysis (Figure 1).^[33d]

Eur. J. Org. Chem. 2015, 3727–3742

www.eurjoc.org

3733

S. A. Babu et al.

FULL PAPER

drous dichloromethane (3 mL) under nitrogen to afford the corre-

sponding crude acid chloride in dichloromethane (DCM). Then,

the acid chloride in DCM was added to a separate flask, which

contained the corresponding amine (1 mmol) and Et₃N (1.1 mmol)

in anhydrous DCM (2 mL). The resulting mixture was then stirred

at room temp. for 12 h. After this period of time, the mixture was

diluted with dichloromethane (5 mL) and then washed with water

followed by a saturated aqueous NaHCO₃solution. The combined

organic layers were dried with anhydrous Na₂SO₄and concentrated

in vacuo. Purification of the resulting reaction mixture by column

chromatography furnished carboxamides 1a–1g and 8a–8d.

ford 1c (188 mg, 74% yield) as a colorless solid; m.p. 85–87 °C. IR

(KBr): ν = 3340, 1658, 1530, 1267, 718 cm^–1. ¹H NMR (400 MHz,

˜

CDCl₃): δ = 10.35 (br. s, 1 H), 8.71 (dd, J₁= 7.6 Hz, J₂= 1.3 Hz,

1 H), 8.62 (dd, J₁= 4.2 Hz, J₂= 1.1 Hz, 1 H), 7.90 (dd, J₁= 8.2 Hz,

J₂= 1.6 Hz, 1 H), 7.66 (dd, J₁= 3.7 Hz, J₂= 1.0 Hz, 1 H), 7.45

(dd, J₁= 4.9 Hz, J₂= 1.0 Hz, 1 H), 7.36 (t, J = 8.1 Hz, 1 H), 7.29

(dd, J₁= 8.3 Hz, J₂= 1.3 Hz, 1 H), 7.21 (dd, J₁= 8.2 Hz, J₂

=

4.2 Hz, 1 H), 7.02 (dd, J₁= 5.0 Hz, J₂= 3.8 Hz, 1 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 159.7, 148.1, 139.0, 138.1, 136.3,

134.0, 131.0, 128.3, 128.0, 127.8, 127.2, 121.7, 121.6, 116.3 ppm.

HRMS (ESI): calcd. for C₁₄H₁₁N₂OS [M + H]⁺255.0592; found

255.0589.

General Procedure for the Direct Arylation and Benzylation of Het-

ereocyclic Carboxamides – The Preparation of 3a–3g, 4a–4c, 5a–5f,

6a–6h, 7a–7d, 9a–9f, 12, and 14: The corresponding heterocyclic

carboxamide (0.25 mmol), Pd(OAc)₂(2.8 mg, 0.0125 mmol, 5 mol-

%), the iodo compound (1.0 mmol), and AgOAc (91.8 mg,

0.55 mmol) in anhydrous toluene (3 mL) was heated at 110 °C for

24–48 h under nitrogen. After the reaction period (see the respec-

tive Tables/Schemes), the mixture was concentrated in vacuo. Puri-

fication of the crude residue by column chromatography on silica

gel furnished the corresponding arylated and benzylated hetereo-

cyclic carboxamides 3a–3g, 4a–4c, 5a–5f, 6a–6h, 7a–7d, 9a–9f, 12,

and 14 (see the corresponding Tables/Schemes for specific details).

N-(Quinolin-8-yl)furan-2-carboxamide (1d):^[23e]Following the gene-

ral procedure yielded the crude product, which was purified by col-

umn chromatography on silica gel (EtOAc/hexane, 20:80) to afford

1d (181 mg, 76% yield) as a pale brown solid; m.p. 138–140 °C. IR

(KBr): ν = 3331, 1673, 1533, 1274, 755 cm^–1. ¹H NMR (400 MHz,

˜

CDCl₃): δ = 10.73 (br. s, 1 H), 8.86 (dd, J₁= 7.4 Hz, J₂= 1.5 Hz,

1 H), 8.83 (dd, J₁= 4.2 Hz, J₂= 1.7 Hz, 1 H), 8.11 (dd, J₁= 8.3 Hz,

J₂= 1.7 Hz, 1 H), 7.60 (dd, J₁= 1.7 Hz, J₂= 0.8 Hz, 1 H), 7.55–

7.47 (m, 2 H), 7.42 (dd, J₁= 8.2 Hz, J₂= 4.2 Hz, 1 H), 7.30 (dd,

J₁= 3.5 Hz, J₂= 0.8 Hz, 1 H), 6.57 (dd, J₁= 3.4 Hz, J₂= 1.7 Hz,

1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 156.3, 148.4, 148.3,

144.6, 138.6, 136.3, 134.1, 128.0, 127.3, 121.8, 121.7, 116.6, 115.1,

112.4 ppm. HRMS (ESI): calcd. for C₁₄H₁₁N₂O₂[M + H]⁺

239.0821; found 239.0813.

General Procedure for the Alkylation of Hetereocyclic Carbox-

amides – The Preparation of 16a–16d: The heterocyclic carbox-

amide (0.25 mmol), Pd(OAc)₂(2.8 mg, 0.0125 mmol, 5 mol-%), the

alkyl iodide (1.0 mmol), K₂CO₃(0.75 mmol, 3 equiv.), and pivalic

acid (20 mol-%) in anhydrous tert-amyl alcohol (0.3 mL) was

heated at 100 °C for 24 h under nitrogen. After the reaction period,

the mixture was concentrated in vacuo. Purification of the crude

residue by column chromatography on silica gel furnished the cor-

responding alkylated hetereocyclic carboxamides 16a–16d (see the

corresponding Scheme/Table for specific details).

N-(Quinolin-8-yl)benzo[b]thiophene-2-carboxamide (1e): Following

the general procedure yielded the crude product, which was puri-

fied by column chromatography on silica gel (EtOAc/hexane, 20:80)

to afford 1e (155 mg, 51% yield) as a colorless solid; m.p. 138–

140 °C. IR (KBr): ν = 3340, 1659, 1529, 1484, 1425 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃): δ = 10.77 (br. s, 1 H), 8.92–8.90 (m, 2 H), 8.22

(dd, J₁= 8.3 Hz, J₂= 1.6 Hz, 1 H), 8.09 (s, 1 H), 7.97–7.93 (m, 2

H), 7.64–7.56 (m, 2 H), 7.52 (dd, J₁= 8.3 Hz, J₂= 4.2 Hz, 1 H),

7.49–7.45 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 160.4,

148.4, 141.4, 139.7, 139.3, 138.5, 136.5, 134.2, 128.0, 127.5, 126.5,

125.4, 125.3, 125.0, 122.8, 122.0, 121.8, 116.7 ppm. HRMS (ESI):

calcd. for C₁₈H₁₃N₂OS [M + H]⁺305.0749; found 305.0750.

N-[2-(Methylthio)phenyl]thiophene-2-carboxamide (1a): Following

the general procedure yielded the crude product, which was puri-

fied by column chromatography on silica gel (EtOAc/hexane, 5:95)

to afford 1a (224 mg, 90% yield) as a colorless solid; m.p. 106–

1

108 °C. IR (KBr): ν = 3368, 1654, 1526, 1306, 752 cm^–1. H NMR

˜

(400 MHz, CDCl₃): δ = 9.12 (br. s, 1 H), 8.45 (dd, J₁= 8.2 Hz, J₂

= 1.1 Hz, 1 H), 7.68 (dd, J₁= 3.8 Hz, J₂= 1.0 Hz, 1 H), 7.55 (dd,

J₁= 5.0 Hz, J₂= 1.1 Hz, 1 H), 7.52 (dd, J₁= 7.8 Hz, J₂= 1.4 Hz,

1 H), 7.33 (td, J₁= 8.5 Hz, J₂= 1.4 Hz, 1 H), 7.14 (dd, J₁= 5.0 Hz,

J₂= 3.8 Hz, 1 H), 7.09 (td, J = 7.6 Hz, J₂= 1.3 Hz, 1 H), 2.39 (s,

3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 159.7, 139.6, 138.3,

131.1, 133.3, 129.2, 128.4, 128.0, 125.4, 124.5, 120.4, 19.2 ppm.

HRMS (ESI): calcd. for C₁₂H₁₂NOS₂[M + H]⁺250.0360; found

250.0362.

N-[2-(Methylthio)phenyl]benzo[b]thiophene-2-carboxamide (1f): Fol-

lowing the general procedure yielded the crude product, which was

purified by column chromatography on silica gel (EtOAc/hexane,

20:80) to afford 1f (209 mg, 70% yield) as a pale orange solid; m.p.

110–112 °C. IR (KBr): ν = 3437, 1663, 1573, 1524, 753 cm^–1. ¹H

˜

NMR (400 MHz, CDCl₃): δ = 9.29 (br. s, 1 H), 8.52 (dd, J₁

=

8.2 Hz, J₂= 1.3 Hz, 1 H), 7.94 (s, 1 H), 7.92–7.89 (m, 2 H), 7.58

(dd, J₁= 7.8 Hz, J₂= 1.5 Hz, 1 H), 7.49–7.42 (m, 2 H), 7.38 (td,

J₁= 7.8 Hz, J₂= 1.5 Hz, 1 H), 7.14 (td, J₁= 7.6 Hz, J₂= 1.4 Hz,

1 H), 2.46 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 160.1,

141.2, 139.1, 139.1, 138.3, 133.5, 129.4, 126.7, 125.6, 125.4, 125.3,

125.1, 124.7, 122.8, 120.4, 19.4 ppm. HRMS (ESI): calcd. for

C₁₆H₁₄NOS₂[M + H]⁺300.0517; found 300.0515.

N-[2-(Methylthio)phenyl]furan-2-carboxamide (1b):^[33a]Following

the general procedure yielded the crude product, which was puri-

fied by column chromatography on silica gel (EtOAc/hexane, 30:70)

to afford 1b (93 mg, 40% yield) as a colorless solid; m.p. 76–78 °C.

IR (KBr): ν = 3326, 1672, 1595, 1530, 751 cm^–1. ¹H NMR

˜

N-[2-(Methylthio)phenyl]benzofuran-2-carboxamide (1g): Following

the general procedure yielded the crude product, which was puri-

fied by column chromatography on silica gel (EtOAc/hexane, 20:80)

(400 MHz, CDCl₃): δ = 9.38 (br. s, 1 H), 8.50 (d, J = 8.2 Hz, 1 H),

7.57 (s, 1 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.34 (t, J = 8.0 Hz, 1 H),

7.26 (d, J = 3.4 Hz, 1 H), 7.10 (t, J = 7.6 Hz, 1 H), 6.58–6.56 (m,

1 H), 2.42 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 156.1,

148.0, 144.6, 138.1, 133.3, 129.1, 125.5, 124.5, 120.4, 115.4, 112.6,

19.1 ppm. HRMS (ESI): calcd. for C₁₂H₁₂NO₂S [M + H]⁺

234.0589; found 234.0589.

N-(Quinolin-8-yl)thiophene-2-carboxamide (1c):^[22d]Following the

general procedure yielded the crude product, which was purified by

column chromatography on silica gel (EtOAc/hexane, 20:80) to af-

to afford 1g (85 mg, 30% yield) as a pale yellow solid; m.p. 76–

1

78 °C. IR (KBr): ν = 3440, 1669, 1581, 1275, 743 cm^–1. H NMR

˜

(400 MHz, CDCl₃): δ = 9.63 (br. s, 1 H), 8.55 (dd, J₁= 8.2 Hz, J₂

= 1.3 Hz, 1 H), 7.75–7.72 (m, 1 H), 7.65–7.63 (m, 2 H), 7.59 (dd,

J₁= 7.8 Hz, J₂= 1.5 Hz, 1 H), 7.51–7.47 (m, 1 H), 7.41–7.33 (m,

2 H), 7.16 (td, J₁= 7.6 Hz, J₂= 1.4 Hz, 1 H), 2.49 (s, 3 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 156.7, 155.0, 148.8, 137.9, 133.3,

129.1, 127.7, 127.3, 125.8, 124.8, 123.9, 122.8, 120.7, 112.1, 111.5,

3734

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Eur. J. Org. Chem. 2015, 3727–3742

Arylation and Alkylation of Thiophene- and Furan-2-carboxamides

19.1 ppm. HRMS (ESI): calcd. for C₁₆H₁₄NO₂S [M + H]⁺

284.0745; found 284.0751.

silica gel (EtOAc/hexane, 20:80) to afford 3e (44 mg, 49% yield) as

a pale yellow solid; m.p. 102–104 °C. IR (KBr): ν = 3318, 1655,

˜

1

1511, 1304, 750 cm^–1. H NMR (400 MHz, CDCl₃): δ = 8.55 (br.

3-(5-Bromopyridin-2-yl)-N-[2-(methylthio)phenyl]thiophene-2-carb-

oxamide (3a): Following the general procedure yielded the crude

product, which was purified by column chromatography on silica

gel (EtOAc/hexane, 20:80) to afford 3a (82 mg, 81% yield) as a pale

s, 1 H), 8.46 (dd, J₁= 5.2 Hz, J₂= 0.6 Hz, 1 H), 8.42 (d, J = 8.2 Hz,

1 H), 7.61 (d, J = 5.1 Hz, 1 H), 7.53 (t, J = 0.8 Hz, 1 H), 7.44 (dd,

J₁= 7.8 Hz, J₂= 1.7 Hz, 1 H), 7.40 (dd, J₁= 5.1 Hz, J₂= 1.5 Hz,

1 H), 7.33–7.29 (m, 1 H), 7.12 (d, J = 5.1 Hz, 1 H), 7.09 (td, J₁=

7.6 Hz, J₂= 1.4 Hz, 1 H), 2.22 (s, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 159.6, 152.2, 150.1, 146.2, 138.7, 137.9, 136.3, 133.0,

130.3, 129.7, 128.9, 125.5, 124.9, 124.5, 123.0, 120.3, 19.3 ppm.

HRMS (ESI): calcd. for C₁₇H₁₄ClN₂OS₂[M + H]⁺361.0236; found

361.0217.

yellow solid; m.p. 162–164 °C. IR (KBr): ν = 3440, 1642, 1471,

˜

1260, 753 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 12.52 (br. s, 1

H), 8.87 (dd, J₁= 2.4 Hz, J₂= 0.6 Hz, 1 H), 8.04 (dd, J₁= 8.1 Hz,

J₂= 1.4 Hz, 1 H), 7.99 (dd, J₁= 8.5 Hz, J₂= 2.4 Hz, 1 H), 7.62

(dd, J₁= 8.5 Hz, J₂= 0.6 Hz, 1 H), 7.59 (d, J = 5.3 Hz, 1 H), 7.41

(dd, J₁= 7.8 Hz, J₂= 1.5 Hz, 1 H), 7.39 (d, J₁= 5.3 Hz, 1 H), 7.26

(dd, J₁= 8.2 Hz, J₂= 1.5 Hz, 1 H), 7.16 (td, J₁= 7.6 Hz, J₂

=

3-(6-Fluoropyridin-3-yl)-N-[2-(methylthio)phenyl]thiophene-2-

carboxamide (3f): Following the general procedure yielded the

crude product, which was purified by column chromatography on

silica gel (EtOAc/hexane, 20:80) to afford 3f (45 mg, 53% yield) as

1.4 Hz, 1 H), 2.47 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 160.5, 152.0, 149.8, 140.9, 140.5, 137.2, 137.0, 130.3, 129.9, 129.5,

129.2, 126.9, 125.3, 125.2, 124.1, 119.8, 17.1 ppm. HRMS (ESI):

calcd. for C₁₇H₁₄BrN₂OS₂[M + H]⁺404.9731; found 404.9712.

a colorless solid; m.p. 114–116 °C. IR (KBr): ν = 3317, 1655, 1578,

˜

1511, 762 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.64 (br. s, 1 H),

8.44 (dd, J₁= 8.3 Hz, J₂= 1.1 Hz, 1 H), 8.41 (d, J = 2.5 Hz, 1 H),

8.00–7.96 (m, 1 H), 7.61 (d, J = 5.1 Hz, 1 H), 7.44 (dd, J₁= 7.8 Hz,

J₂= 1.5 Hz, 1 H), 7.33–7.29 (m, 1 H), 7.12 (d, J = 5.1 Hz, 1 H),

7.09 (dd, J₁= 7.6 Hz, J₂= 1.4 Hz, 1 H), 7.06–7.04 (m, 1 H), 2.20

3-(4-Acetylphenyl)-N-[2-(methylthio)phenyl]thiophene-2-carbox-

amide (3b): Following the general procedure yielded the crude prod-

uct, which was purified by column chromatography on silica gel

(EtOAc/hexane, 20:80) to afford 3b (62 mg, 68% yield) as a pale

yellow solid; m.p. 121–123 °C. IR (KBr): ν = 3314, 1680, 1511,

˜

(s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 163.5 (d, J_C,F

=

1265, 761 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.57 (br. s, 1 H),

8.45 (dd, J₁= 8.3 Hz, J₂= 1.1 Hz, 1 H), 8.04 (d, J = 8.5 Hz, 2 H),

7.64 (d, J = 8.5 Hz, 2 H), 7.57 (d, J = 5.0 Hz, 1 H), 7.37 (dd, J₁=

7.8 Hz, J₂= 1.5 Hz, 1 H), 7.28 (td, J₁= 8.8 Hz, J₂= 1.4 Hz, 1 H),

7.12 (d, J = 5.0 Hz, 1 H), 7.04 (td, J₁= 7.6 Hz, J₂= 1.4 Hz, 1 H),

2.63 (s, 3 H), 2.03 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 197.6, 160.2, 141.7, 139.9, 138.2, 137.0, 135.5, 133.2, 131.0, 129.8,

129.5, 129.0, 128.9, 125.3, 124.6, 120.4, 26.8, 19.3 ppm. HRMS

(ESI): calcd. for C₂₀H₁₈NO₂S₂[M + H]⁺368.0779; found 368.0770.

239.9 Hz), 159.9, 147.8, 147.7, 142.4 (d, J_C,F= 8.0 Hz), 138.2 (d,

J_C,F= 10.5 Hz), 135.5, 133.2, 131.0, 129.5, 129.2 (d, J_C,F= 4.8 Hz),

129.0, 125.1, 124.7, 120.2, 109.9 (d, J_C,F= 37.3 Hz), 19.4 ppm.

HRMS (ESI): calcd. for C₁₇H₁₄FN₂OS₂[M + H]⁺345.0532; found

345.0540.

N-[2-(Methylthio)phenyl]-[2,3Ј-bithiophene]-2Ј-carboxamide (3g):

Following the general procedure yielded the crude product, which

was purified by column chromatography on silica gel (EtOAc/hex-

ane, 20:80) to afford 3g (68 mg, 82% yield) as a green, thick liquid.

3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-N-[2-(methylthio)phenyl]-

thiophene-2-carboxamide (3c): Following the general procedure

yielded the crude product, which was purified by column

chromatography on silica gel (EtOAc/hexane, 20:80) to afford 3c

(63 mg, 66% yield) as a pale yellow solid; m.p. 113–115 °C. IR

IR (DCM): ν = 3300, 1653, 1578, 1517, 759 cm^{–1 1}H NMR

.

˜

(400 MHz, CDCl₃): δ = 9.02 (br. s, 1 H), 8.47 (dd, J₁= 8.3 Hz, J₂

= 1.2 Hz, 1 H), 7.53 (d, J = 5.1 Hz, 1 H), 7.46–7.42 (m, 2 H), 7.34–

7.30 (m, 2 H), 7.15 (d, J = 5.1 Hz, 1 H), 7.12 (dd, J₁= 5.2 Hz, J₂

= 3.5 Hz, 1 H), 7.07 (td, J₁= 7.6 Hz, J₂= 1.4 Hz, 1 H), 2.17 (s, 3

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 160.3, 138.4, 135.7,

135.5, 134.5, 133.3, 131.9, 129.1, 128.9, 128.8, 128.1, 127.6, 125.6,

124.5, 120.8, 19.6 ppm. HRMS (ESI): calcd. for C₁₆H₁₄NOS₃[M

+ H]⁺332.0238; found 332.0225.

(KBr): ν = 3437, 1651, 1579, 1511, 1260, 764 cm^{–1 1}H NMR

.

˜

(400 MHz, CDCl₃): δ = 8.78 (br. s, 1 H), 8.47 (d, J = 8.2 Hz, 1 H),

7.52 (d, J = 5.0 Hz, 1 H), 7.41 (dd, J₁= 7.8 Hz, J₂= 1.4 Hz, 1 H),

7.32–7.28 (m, 1 H), 7.05–6.93 (m, 5 H), 4.32–4.28 (m, 4 H), 2.12

(s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 160.6, 144.4,

144.1, 142.2, 138.7, 135.0, 133.4, 131.6, 129.4, 128.9, 128.2, 125.3,

124.3, 122.7, 120.7, 118.4, 118.1, 64.5, 64.4, 19.4 ppm. HRMS

(ESI): calcd. for C₂₀H₁₈NO₃S₂[M + H]⁺384.0728; found 384.0745.

3-(4-Acetylphenyl)-N-[2-(methylthio)phenyl]furan-2-carboxamide

(4a): Following the general procedure yielded the crude product,

which was purified by column chromatography on silica gel

(EtOAc/hexane, 20:80) to afford 4a (35 mg, 40% yield) as a pale

3-(2,4-Dimethoxyphenyl)-N-[2-(methylthio)phenyl]thiophene-2-

carboxamide (3d): Following the general procedure yielded the

crude product, which was purified by column chromatography on

silica gel (EtOAc/hexane, 20:80) to afford 3d (24 mg, 25% yield) as

brown solid; m.p. 110–112 °C. IR (KBr): ν = 3332, 1679, 1580,

˜

1518, 750 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.48 (br. s, 1 H),

8.46 (dd, J₁= 8.2 Hz, J₂= 1.3 Hz, 1 H), 8.05 (d, J = 8.5 Hz, 2 H),

7.87 (d, J = 8.5 Hz, 2 H), 7.65 (d, J = 1.8 Hz, 1 H), 7.55 (dd, J₁=

7.8 Hz, J₂= 1.5 Hz, 1 H), 7.34–7.30 (m, 1 H), 7.11 (td, J₁= 7.6 Hz,

J₂= 1.4 Hz, 1 H), 6.75 (d, J = 1.8 Hz, 1 H), 2.66 (s, 3 H), 2.45 (s,

3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 197.8, 156.4, 143.6,

142.0, 138.1, 136.6, 136.6, 133.2, 131.5, 129.7, 129.0, 128.2, 125.6,

124.5, 120.6, 114.8, 26.7, 19.1 ppm. HRMS (ESI): calcd. for

C₂₀H₁₈NO₃S [M + H]⁺352.1007; found 352.1019.

a yellow, thick liquid. IR (KBr): ν = 3305, 1653, 1512, 1208,

˜

1

763 cm^–1. H NMR (400 MHz, CDCl₃): δ = 8.77 (br. s, 1 H), 8.48

(dd, J₁= 8.3 Hz, J₂= 1.2 Hz, 1 H), 7.53 (d, J = 5.1 Hz, 1 H), 7.39

(dd, J₁= 7.7 Hz, J₂= 1.6 Hz, 1 H), 7.32–7.26 (m, 2 H), 7.04 (d, J

= 5.0 Hz, 1 H), 7.01 (dd, J₁= 7.6 Hz, J₂= 1.3 Hz, 1 H), 6.60 (dd,

J₁= 8.4 Hz, J₂= 2.4 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 3.86 (s,

3 H), 3.73 (s, 3 H), 2.08 (s, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 161.9, 161.1, 158.2, 138.8, 138.2, 136.0, 133.2, 132.1,

131.9, 128.8, 128.7, 125.2, 124.0, 120.5, 116.2, 105.2, 99.5, 55.7,

55.5, 19.3 ppm. HRMS (ESI): calcd. for C₂₀H₁₉NNaO₃S₂[M +

Na]⁺408.0704; found 408.0683.

3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-N-[2-(methylthio)phenyl]-

furan-2-carboxamide (4b): Following the general procedure yielded

the crude product, which was purified by column chromatography

on silica gel (EtOAc/hexane, 20:80) to afford 4b (35 mg, 38% yield)

3-(2-Chloropyridin-4-yl)-N-[2-(methylthio)phenyl]thiophene-2-

carboxamide (3e): Following the general procedure yielded the

crude product, which was purified by column chromatography on

as a colorless solid; m.p. 157–159 °C. IR (KBr): ν = 3334, 2923,

˜

1

1674, 1579, 1511 cm^–1. H NMR (400 MHz, CDCl₃): δ = 9.37 (br.

s, 1 H), 8.50 (d, J = 8.2 Hz, 1 H), 7.57 (d, J = 1.2 Hz, 1 H), 7.53

Eur. J. Org. Chem. 2015, 3727–3742

www.eurjoc.org

3735

S. A. Babu et al.

FULL PAPER

(d, J = 7.6 Hz, 1 H), 7.34–7.26 (m, 3 H), 7.09 (t, J = 7.5 Hz, 1 H), 31.0 Hz), 137.9, 136.8, 136.2, 134.0, 130.9, 129.9, 129.3 (d, J_C,F

6.95 (d, J = 8.3 Hz, 1 H), 6.66 (d, J = 1.2 Hz, 1 H), 4.31 (s, 4 H), 4.6 Hz), 127.8, 127.3, 121.9, 121.7, 116.4, 109.9 (d, J_C,F

=

2.41 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 156.7, 143.9, 37.7 Hz) ppm. HRMS (ESI): calcd. for C₁₉H₁₃FN₃OS [M + H]⁺

143.3, 143.2, 141.2, 138.5, 133.3, 132.0, 129.0, 125.4, 124.8, 124.2,

122.9, 120.6, 118.4, 117.1, 114.9, 64.5, 64.3, 19.1 ppm. HRMS

(ESI): calcd. for C₂₀H₁₈NO₄S [M + H]⁺368.0957; found 368.0950.

350.0763; found 350.0763.

3-(6-Chloropyridin-3-yl)-N-(quinolin-8-yl)thiophene-2-carboxamide

(5d): Following the general procedure yielded the crude product,

which was purified by column chromatography on silica gel

(EtOAc/hexane, 20:80) to afford 5d (56 mg, 62% yield) as a yellow

3-(5-Bromopyridin-2-yl)-N-[2-(methylthio)phenyl]furan-2-carb-

oxamide (4c): Following the general procedure yielded the crude

product, which was purified by column chromatography on silica

gel (EtOAc/hexane, 20:80) to afford 4c (39 mg, 40% yield) as a pale

solid; m.p. 186–188 °C. IR (KBr): ν = 3385, 1651, 1527, 1454,

˜

766 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.03 (br. s, 1 H), 8.78

(dd, J₁= 7.2 Hz, J₂= 1.5 Hz, 1 H), 8.63 (d, J = 2.4 Hz, 1 H), 8.52

(dd, J₁= 4.2 Hz, J₂= 1.4 Hz, 1 H), 8.12 (d, J = 8.2 Hz, 1 H), 7.85

(dd, J₁= 8.2 Hz, J₂= 2.4 Hz, 1 H), 7.64 (d, J = 5.0 Hz, 1 H), 7.56–

7.49 (m, 2 H), 7.42–7.39 (m, 2 H), 7.14 (d, J = 5.0 Hz, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 159.8, 151.4, 149.7, 148.0, 139.9,

138.2, 137.8, 136.9, 136.2, 134.0, 130.8, 130.3, 129.9, 127.8, 127.3,

124.6, 122.0, 121.7, 116.4 ppm. HRMS (ESI): calcd. for

C₁₉H₁₃ClN₃OS [M + H]⁺366.0468; found 366.0478.

brown solid; m.p. 154–156 °C. IR (KBr): ν = 3346, 1670, 1580,

˜

1521, 754 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 11.76 (br. s, 1

H), 8.82 (t, J = 1.5 Hz, 1 H), 8.18 (dd, J₁= 8.1 Hz, J₂= 1.2 Hz, 1

H), 7.96 (d, J = 1.6 Hz, 2 H), 7.68 (d, J = 1.8 Hz, 1 H), 7.46 (dd,

J₁= 7.8 Hz, J₂= 1.4 Hz, 1 H), 7.33–7.29 (m, 1 H), 7.16 (td, J₁=

7.6 Hz, J₂= 1.3 Hz, 1 H), 7.00 (d, J = 1.8 Hz, 1 H), 2.48 (s, 3

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 156.9, 149.9, 148.9,

144.4, 144.2, 139.9, 137.1, 130.5, 128.4, 127.6, 125.2, 125.2, 123.2,

119.8, 113.0, 17.6 ppm. HRMS (ESI): calcd. for C₁₇H₁₄BrN₂O₂S

[M + H]⁺388.9959; found 388.9973.

3-(5-Bromopyridin-2-yl)-N-(quinolin-8-yl)thiophene-2-carboxamide

(5e): Following the general procedure yielded the crude product,

which was purified by column chromatography on silica gel

(EtOAc/hexane, 20:80) to afford 5e (63 mg, 62% yield) as a pale

3-(4-Acetylphenyl)-N-(quinolin-8-yl)thiophene-2-carboxamide (5a):

Following the general procedure yielded the crude product, which

was purified by column chromatography on silica gel gel (EtOAc/

hexane, 20:80) to afford 5a (65 mg, 70% yield) as a yellow solid;

yellow solid; m.p. 157–159 °C. IR (KBr): ν = 3399, 1623, 1546,

˜

1276, 762 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 13.14 (br. s, 1

H), 9.01 (dd, J₁= 2.4 Hz, J₂= 0.6 Hz, 1 H), 8.97 (dd, J₁= 6.7 Hz,

J₂= 2.4 Hz, 1 H), 8.90 (dd, J₁= 4.2 Hz, J₂= 1.7 Hz, 1 H), 8.20

m.p. 159–161 °C. IR (KBr): ν = 3305, 1681, 1647, 1527, 1265 cm^–1.

˜

¹H NMR (400 MHz, CDCl₃): δ = 9.97 (br. s, 1 H), 8.81 (dd, J₁=

7.6 Hz, J₂= 1.4 Hz, 1 H), 8.19 (dd, J₁= 4.2 Hz, J₂= 1.7 Hz, 1 H),

8.06 (d, J = 1.6 Hz, 1 H), 8.03 (d, J = 8.5 Hz, 2 H), 7.66 (d, J =

8.5 Hz, 2 H), 7.60 (d, J = 5.1 Hz, 1 H), 7.51 (t, J = 8.2 Hz, 1 H),

7.46 (dd, J₁= 8.2 Hz, J₂= 1.4 Hz, 1 H), 7.29 (dd, J₁= 8.2 Hz, J₂

= 4.2 Hz, 1 H), 7.14 (d, J = 5.0 Hz, 1 H), 2.60 (s, 3 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 197.9, 160.3, 147.5, 141.9, 140.1,

138.3, 136.8, 136.2, 136.0, 134.2, 130.9, 129.9, 129.6, 129.0, 127.8,

127.3, 121.8, 121.5, 116.5, 26.8 ppm. HRMS (ESI): calcd. for

C₂₂H₁₇N₂O₂S [M + H]⁺373.1011; found 373.1009.

(dd, J₁= 8.3 Hz, J₂= 1.7 Hz, 1 H), 7.96 (dd, J₁= 8.4 Hz, J₂

=

2.4 Hz, 1 H), 7.62–7.55 (m, 4 H), 7.52 (dd, J₁= 8.3 Hz, J₂= 4.2 Hz,

1 H), 7.38 (d, J = 5.3 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 160.8, 152.3, 150.5, 148.3, 140.9, 140.1, 139.7, 137.9, 136.4,

135.6, 130.2, 129.8, 128.3, 127.4, 125.0, 122.3, 121.5, 119.6,

118.7 ppm. HRMS (ESI): calcd. for C₁₉H₁₃BrN₃OS [M + H]⁺

409.9963; found 409.9975.

N-(Quinolin-8-yl)-[2,3Ј-bithiophene]-2Ј-carboxamide (5f): Following

the general procedure yielded the crude product, which was puri-

fied by column chromatography on silica gel (EtOAc/hexane, 20:80)

to afford 5f (54 mg, 64% yield) as a yellow solid; m.p. 107–109 °C.

3-(4-Methoxyphenyl)-N-(quinolin-8-yl)thiophene-2-carboxamide

(5b):^[29]Following the general procedure yielded the crude product,

which was purified by column chromatography on silica gel

(EtOAc/hexane, 20:80) to afford 5b (71 mg, 79% yield) as a color-

IR (KBr): ν = 3285, 1647, 1526, 1268, 790 cm^–^{1 1}H NMR

.

˜

(400 MHz, CDCl₃): δ = 10.50 (br. s, 1 H), 8.87 (dd, J₁= 7.5 Hz,

J₂= 1.4 Hz, 1 H), 8.50 (dd, J₁= 4.2 Hz, J₂= 1.7 Hz, 1 H), 8.10

(dd, J₁= 8.3 Hz, J₂= 1.7 Hz, 1 H), 7.57–7.53 (m, 2 H), 7.51–7.48

(m, 2 H), 7.38–7.35 (m, 2 H), 7.19 (d, J = 5.0 Hz, 1 H), 7.15 (dd,

J₁= 5.1 Hz, J₂= 3.6 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 160.3, 147.8, 138.6, 136.4, 136.0, 135.3, 134.7, 134.4, 132.0,

129.1, 129.0, 127.9, 127.8, 127.4, 127.2, 121.7, 121.5, 116.6 ppm.

HRMS (ESI): calcd. for C₁₈H₁₃N₂OS₂[M + H]⁺337.0469; found

337.0461.

less solid; m.p. 188–190 °C. IR (KBr): ν = 3344, 2949, 1687, 1579,

˜

1431, 754 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.17 (br. s, 1

H), 8.86 (dd, J₁= 7.6 Hz, J₂= 1.4 Hz, 1 H), 8.32 (dd, J₁= 4.2 Hz,

J₂= 1.7 Hz, 1 H), 8.05 (dd, J₁= 8.3 Hz, J₂= 1.7 Hz, 1 H), 7.56

(d, J = 5.0 Hz, 1 H), 7.53–7.45 (m, 2 H), 7.50 (d, J = 8.8 Hz, 2 H),

7.32 (dd, J₁= 8.2 Hz, J₂= 4.2 Hz, 1 H), 7.10 (d, J = 5.0 Hz, 1 H),

7.01 (d, J = 8.8 Hz, 2 H), 3.85 (s, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 160.8, 160.1, 147.4, 142.9, 138.4, 135.9, 135.4, 134.6,

131.6, 130.8, 129.3, 127.7, 127.4, 127.4, 121.4, 121.4, 116.4, 114.6,

55.4 ppm. HRMS (ESI): calcd. for C₂₁H₁₇N₂O₂S [M + H]⁺

361.1011; found 361.1021.

3-(4-Acetylphenyl)-N-(quinolin-8-yl)furan-2-carboxamide (6a): Fol-

lowing the general procedure yielded the crude product, which was

purified by column chromatography on silica gel (EtOAc/hexane,

3-(6-Fluoropyridin-3-yl)-N-(quinolin-8-yl)thiophene-2-carboxamide

(5c): Following the general procedure yielded the crude product,

which was purified by column chromatography on silica gel

(EtOAc/hexane, 20:80) to afford 5c (64 mg, 73% yield) as a pale

20:80) to afford 6a (60 mg, 67% yield) as a yellow solid; m.p. 192–

1

194 °C. IR (KBr): ν = 3358, 1668, 1592, 1525, 754 cm^–1. H NMR

˜

(400 MHz, CDCl₃): δ = 10.90 (br. s, 1 H), 8.89–8.85 (m, 2 H), 8.21

yellow solid; m.p. 189–191 °C. IR (KBr): ν = 3440, 1649, 1526, (dd, J₁= 8.3 Hz, J₂= 1.7 Hz, 1 H), 8.07 (d, J = 8.6 Hz, 2 H), 7.90

˜

1250, 763 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.02 (br. s, 1

(d, J = 8.6 Hz, 2 H), 7.71 (d, J = 1.8 Hz, 1 H), 7.56 (d, J = 4.4 Hz,

H), 8.79 (dd, J₁= 7.3 Hz, J₂= 1.6 Hz, 1 H), 8.49–8.47 (m, 2 H), 2 H), 7.51 (dd, J₁= 8.2 Hz, J₂= 4.2 Hz, 1 H), 6.76 (d, J = 1.8 Hz,

8.12 (dd, J₁= 8.3 Hz, J₂= 1.7 Hz, 1 H), 8.00–7.96 (m, 1 H), 7.64

(d, J = 5.0 Hz, 1 H), 7.56–7.48 (m, 2 H), 7.40 (dd, J₁= 8.3 Hz, J₂

1 H), 2.67 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 197.9,

156.6, 148.4, 143.6, 142.3, 138.7, 136.8, 136.5, 136.4, 134.2, 131.2,

= 4.2 Hz, 1 H), 7.15 (d, J = 5.0 Hz, 1 H), 7.04–7.01 (m, 1 H) ppm. 129.8, 128.2, 128.0, 127.4, 121.9, 121.7, 116.8, 114.7, 26.8 ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 163.7 (d, J_C,F= 239.0 Hz),

159.9, 147.9, 147.8, 142.5 (d, J_C,F= 8.3 Hz), 138.1 (d, J_C,F

HRMS (ESI): calcd. for C₂₂H₁₇N₂O₃[M + H]⁺357.1239; found

357.1242.

=

3736

www.eurjoc.org

Eur. J. Org. Chem. 2015, 3727–3742

Arylation and Alkylation of Thiophene- and Furan-2-carboxamides

3-(4-Methoxyphenyl)-N-(quinolin-8-yl)furan-2-carboxamide (6b):

Following the general procedure yielded the crude product, which

was purified by column chromatography on silica gel (EtOAc/hex-

ane, 20:80) to afford 6f (21 mg, 24% yield) as a yellow solid; m.p.

217–219 °C. IR (KBr): ν = 3401, 1663, 1531, 1260, 778 cm^–1. ¹H

˜

ane, 20:80) to afford 6b (47 mg, 55% yield) as a dark brown solid; NMR (400 MHz, CDCl₃): δ = 10.91 (br. s, 1 H), 8.91 (dd, J₁

=

m.p. 170–172 °C. IR (KBr): ν = 3390, 1676, 1516, 1252, 1040 cm^–1. 4.2 Hz, J₂= 1.6 Hz, 1 H), 8.85–8.81 (m, 1 H), 8.68 (d, J = 2.2 Hz,

˜

¹H NMR (400 MHz, CDCl₃): δ = 10.81 (br. s, 1 H), 8.90 (dd, J₁= 1 H), 8.28 (dd, J₁= 8.3 Hz, J₂= 2.5 Hz, 1 H), 8.21 (dd, J₁= 8.2 Hz,

6.9 Hz, J₂= 1.9 Hz, 1 H), 8.85 (dd, J₁= 4.1 Hz, J₂= 1.4 Hz, 1 H), J₂= 1.6 Hz, 1 H), 7.72 (d, J = 1.8 Hz, 1 H), 7.57 (d, J = 4.3 Hz, 2

8.18 (dd, J₁= 8.2 Hz, J₂= 1.4 Hz, 1 H), 7.76 (d, J = 8.7 Hz, 2 H),

7.65 (d, J = 1.6 Hz, 1 H), 7.58–7.52 (m, 2 H), 7.48 (dd, J₁= 8.2 Hz, 1 H), 6.75 (d, J = 1.8 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

J₂= 4.2 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 2 H), 6.70 (d, J = 1.6 Hz, 1 δ = 156.5, 151.0, 149.5, 148.5, 143.9, 142.7, 140.1, 138.7, 136.4,

H), 7.52 (dd, J₁= 8.2 Hz, J₂= 4.2 Hz, 1 H), 7.44 (d, J = 8.3 Hz,

H), 3.89 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 159.7, 134.1, 128.1, 127.6, 127.4, 127.0, 123.7, 122.1, 121.8, 116.8,

157.1, 148.3, 143.3, 141.5, 138.7, 136.3, 134.5, 132.1, 130.8, 128.0,

127.4, 124.1, 121.6, 121.6, 116.7, 114.8, 113.7, 55.4 ppm. HRMS

(ESI): calcd. for C₂₁H₁₇N₂O₃[M + H]⁺345.1239; found 345.1252.

114.2 ppm. HRMS (ESI): calcd. for C₁₉H₁₃ClN₃O₂[M + H]⁺

350.0696; found 350.0686.

3-(5-Bromopyridin-2-yl)-N-(quinolin-8-yl)furan-2-carboxamide (6g):

Following the general procedure yielded the crude product, which

was purified by column chromatography on silica gel (EtOAc/hex-

ane, 20:80) to afford 6g (59 mg, 60% yield) as a pale brown solid;

Methyl 4-[2-(Quinolin-8-ylcarbamoyl)furan-3-yl]benzoate (6c): Fol-

lowing the general procedure yielded the crude product, which was

purified by column chromatography on silica gel (EtOAc/hexane,

20:80) to afford 6c (62 mg, 67% yield) as a pale yellow solid; m.p.

m.p. 172–174 °C. IR (KBr): ν = 3434, 1652, 1544, 1046, 784 cm^–1.

˜

1

169–171 °C. IR (KBr): ν = 3335, 1723, 1669, 1533, 1278 cm^–1. H ¹H NMR (400 MHz, CDCl₃): δ = 12.59 (br. s, 1 H), 8.96 (dd, J₁=

˜

NMR (400 MHz, CDCl₃): δ = 10.86 (br. s, 1 H), 8.87–8.85 (m, 2

H), 8.18 (dd, J₁= 8.2 Hz, J₂= 1.7 Hz, 1 H), 8.14 (d, J = 8.6 Hz,

2 H), 7.87 (d, J = 8.6 Hz, 2 H), 7.69 (d, J = 1.8 Hz, 1 H), 7.57–

7.53 (m, 2 H), 7.48 (dd, J₁= 8.2 Hz, J₂= 4.2 Hz, 1 H), 6.74 (d, J

= 1.8 Hz, 1 H), 3.97 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 166.9, 156.6, 148.4, 143.6, 142.3, 138.7, 136.6, 136.4, 134.2,

131.2, 129.7, 129.6, 129.5, 128.0, 127.4, 121.9, 121.7, 116.8, 114.7,

52.2 ppm. HRMS (ESI): calcd. for C₂₂H₁₆NaN₂O₄[M + Na]⁺

395.1008; found 395.1028.

7.2 Hz, J₂= 1.9 Hz, 1 H), 8.90 (dd, J₁= 4.2 Hz, J₂= 1.7 Hz, 1 H),

8.88 (dd, J₁= 2.4 Hz, J₂= 0.6 Hz, 1 H), 8.16 (dd, J₁= 8.3 Hz, J₂

= 1.7 Hz, 1 H), 8.02 (dd, J₁= 8.5 Hz, J₂= 0.6 Hz, 1 H), 7.90 (dd,

J₁= 8.5 Hz, J₂= 2.4 Hz, 1 H), 7.67 (d, J = 1.8 Hz, 1 H), 7.59–7.52

(m, 2 H), 7.47 (dd, J₁= 8.2 Hz, J₂= 4.2 Hz, 1 H), 7.00 (d, J =

1.9 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 157.1, 150.2,

149.1, 148.4, 144.4, 144.0, 139.5, 139.3, 136.4, 135.1, 128.4, 128.2,

127.4, 125.3, 122.2, 121.6, 119.7, 118.1, 113.1 ppm. HRMS (ESI):

calcd. for C₁₉H₁₃BrN₃O₂[M + H]⁺394.0191; found 394.0202.

3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-N-(quinolin-8-yl)furan-2- N-(Quinolin-8-yl)-3-(thiophen-2-yl)furan-2-carboxamide (6h): Fol-

carboxamide (6d): Following the general procedure yielded the

crude product, which was purified by column chromatography on

silica gel (EtOAc/hexane, 20:80) to afford 6d (32 mg, 34% yield) as

lowing the general procedure yielded the crude product, which was

purified by column chromatography on silica gel (EtOAc/hexane,

20:80) to afford 6h (47 mg, 59% yield) as a yellow solid; m.p. 154–

1

a black solid; m.p. 147–149 °C. IR (KBr): ν = 3401, 1671, 1528, 156 °C. IR (KBr): ν = 3331, 1673, 1533, 1274, 755 cm^–1. H NMR

˜

1248, 780 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.79 (br. s, 1

(400 MHz, CDCl₃): δ = 10.89 (br. s, 1 H), 8.96 (dd, J₁= 7.3 Hz,

H), 8.91 (dd, J₁= 7.0 Hz, J₂= 2.0 Hz, 1 H), 8.85 (dd, J₁= 4.2 Hz, J₂= 1.7 Hz, 1 H), 8.90 (dd, J₁= 4.2 Hz, J₂= 1.6 Hz, 1 H), 8.21

J₂= 1.6 Hz, 1 H), 8.18 (dd, J₁= 8.2 Hz, J₂= 1.6 Hz, 1 H), 7.63

(d, J = 1.8 Hz, 1 H), 7.58–7.51 (m, 2 H), 7.48 (dd, J₁= 8.2 Hz, J₂

= 4.2 Hz, 1 H), 7.35 (d, J = 2.1 Hz, 1 H), 7.32 (dd, J₁= 8.3 Hz, J₂

(dd, J₁= 8.3 Hz, J₂= 1.7 Hz, 1 H), 7.93 (dd, J₁= 3.7 Hz, J₂

1.2 Hz, 1 H), 7.62 (d, J = 1.8 Hz, 1 H), 7.62–7.54 (m, 2 H), 7.50

(dd, J₁= 8.2 Hz, J₂= 4.2 Hz, 1 H), 7.44 (dd, J₁= 5.1 Hz, J₂

=

= 2.2 Hz, 1 H), 6.98 (d, J = 8.3 Hz, 1 H), 6.68 (d, J = 1.8 Hz, 1 1.2 Hz, 1 H), 7.16 (dd, J₁= 5.1 Hz, J₂= 3.7 Hz, 1 H), 6.87 (d, J =

H), 4.34–4.29 (m, 4 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 1.8 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 157.0, 148.4,

156.9, 148.2, 143.8, 143.3, 143.2, 141.6, 138.8, 136.3, 134.5, 131.8,

128.0, 127.4, 125.1, 123.0, 121.6, 121.5, 118.5, 117.1, 116.7, 114.8,

143.3, 140.8, 138.8, 136.4, 134.4, 133.1, 129.1, 128.1, 127.4, 127.2,

125.7, 121.7, 121.7, 116.7, 113.9 ppm. HRMS (ESI): calcd. for

64.5, 64.4 ppm. HRMS (ESI): calcd. for C₂₂H₁₇N₂O₄[M + H]⁺C₁₈H₁₃N₂O₂S [M + H]⁺321.0698; found 321.0705.

373.1188; found 373.1174.

3-(4-Acetylphenyl)-N-(quinolin-8-yl)benzo[b]thiophene-2-carbox-

3-(6-Fluoropyridin-3-yl)-N-(quinolin-8-yl)furan-2-carboxamide (6e):

Following the general procedure yielded the crude product, which

was purified by column chromatography on silica gel (EtOAc/hex-

amide (7a): Following the general procedure yielded the crude prod-

uct, which was purified by column chromatography on silica gel

(EtOAc/hexane, 20:80) to afford 7a (47 mg, 45% yield) as a pale

ane, 20:80) to afford 6e (37 mg, 44% yield) as a pale yellow solid; yellow solid; m.p. 188–190 °C. IR (KBr): ν = 3300, 2922, 1680,

˜

m.p. 197–199 °C. IR (KBr): ν = 3342, 1673, 1539, 1242, 773 cm^–1. 1648, 1527, 1425, 1054 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

˜

¹H NMR (400 MHz, CDCl₃): δ = 10.91 (br. s, 1 H), 8.90 (dd, J₁= 10.06 (br. s, 1 H), 8.86 (dd, J₁= 7.5 Hz, J₂= 1.5 Hz, 1 H), 8.24

4.2 Hz, J₂= 1.6 Hz, 1 H), 8.83 (t, J = 4.5 Hz, 1 H), 8.52 (dd, J₁= (dd, J₁= 4.2 Hz, J₂= 1.7 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 2 H), 8.08

1.8 Hz, J₂= 0.8 Hz, 1 H), 8.43–8.39 (m, 1 H), 8.20 (dd, J₁= 8.3 Hz,

J₂= 1.7 Hz, 1 H), 7.72 (d, J = 1.8 Hz, 1 H), 7.57 (d, J = 4.4 Hz, 2

(dd, J₁= 8.9 Hz, J₂= 1.7 Hz, 1 H), 7.99–7.97 (m, 1 H), 7.74 (d, J

= 8.4 Hz, 2 H), 7.56–7.47 (m, 4 H), 7.43–7.39 (m, 1 H), 7.32 (dd,

H), 7.51 (dd, J₁= 8.2 Hz, J₂= 4.2 Hz, 1 H), 7.07–7.04 (m, 1 H), J₁= 8.3 Hz, J₂= 4.2 Hz, 1 H), 2.68 (s, 3 H) ppm. ¹³C NMR

6.75 (d, J = 1.8 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = (100 MHz, CDCl₃): δ = 198.0, 160.6, 147.5, 140.3, 140.1, 138.8,

163.3 (d, J_C,F= 239.0 Hz), 156.6, 148.5, 147.7 (d, J_C,F= 14.9 Hz), 138.4, 137.4, 137.0, 136.7, 136.1, 134.2, 130.8, 129.4, 127.8, 127.3,

143.8, 142.7 (d, J_C,F= 8.0 Hz), 142.4, 138.7, 136.4, 134.1, 128.1, 126.8, 125.1, 124.5, 122.7, 121.9, 121.5, 116.7, 26.8 ppm. HRMS

127.7, 127.3, 126.0 (d, J_C,F= 4.8 Hz), 122.0, 121.8, 116.8, 114.3, (ESI): calcd. for C₂₆H₁₉N₂O₂S [M + H]⁺423.1167; found 423.1181.

108.9 (d, J_{C , F}= 37.2 Hz) ppm. HRMS (ESI): calcd. for

3-(5-Bromopyridin-2-yl)-N-[2-(methylthio)phenyl]benzo[b]thioph-

C₁₉H₁₃FN₃O₂[M + H]⁺334.0992; found 334.0976.

ene-2-carboxamide (7b): Following the general procedure yielded

3-(2-Chloropyridin-4-yl)-N-(quinolin-8-yl)furan-2-carboxamide (6f):

the crude product, which was purified by column chromatography

Following the general procedure yielded the crude product, which

on silica gel (EtOAc/hexane, 20:80) to afford 7b (48 mg, 42% yield)

Eur. J. Org. Chem. 2015, 3727–3742

www.eurjoc.org

3737

S. A. Babu et al.

FULL PAPER

as a pale yellow solid; m.p. 164–166 °C. IR (KBr): ν = 3400, 1684,

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 161.9, 139.4, 129.6,

˜

1

1441, 1265, 756 cm^–1. H NMR (400 MHz, CDCl₃): δ = 10.20 (br. 127.8, 127.6, 51.4, 46.8, 37.3, 11.9 ppm. HRMS (ESI): calcd. for

s, 1 H), 8.95 (d, J = 2.2 Hz, 1 H), 8.24 (d, J = 8.2 Hz, 1 H), 8.04 C₁₁H₁₉N₂OS [M + H]⁺227.1218; found 227.1213.

(dd, J₁= 8.3 Hz, J₂= 2.2 Hz, 1 H), 7.95 (d, J = 8.1 Hz, 1 H), 7.69

N-Phenylthiophene-2-carboxamide (8c): Following the general pro-

(d, J = 8.2 Hz, 1 H), 7.59 (d, J = 8.3 Hz, 1 H), 7.51 (t, J = 7.6 Hz,

cedure yielded the crude product, which was purified by column

chromatography on silica gel (EtOAc/hexane, 20:80) to afford 8c

1 H), 7.45–7.41 (m, 2 H), 7.31–7.27 (m, 1 H), 7.13 (t, J = 7.5 Hz,

1 H), 2.38 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 160.8,

(88 mg, 44% yield) as a white solid; m.p. 134–136 °C. IR (KBr): ν

˜

151.4, 151.2, 139.8, 139.8, 139.3, 138.8, 137.5, 134.3, 131.6, 128.0,

127.3, 127.2, 126.7, 125.3, 125.2, 124.2, 122.6, 122.2, 120.7,

18.4 ppm. HRMS (ESI): calcd. for C₂₁H₁₆BrN₂OS₂[M + H]⁺

454.9887; found 454.9895.

1

= 3421, 1631, 1596, 1534, 752 cm^–1. H NMR (400 MHz, CDCl₃):

δ = 7.96 (br. s, 1 H), 7.67 (dd, J₁= 3.7 Hz, J₂= 1.1 Hz, 1 H), 7.65–

7.63 (m, 2 H), 7.55 (dd, J₁= 5.0 Hz, J₂= 1.1 Hz, 1 H), 7.39–7.34

(m, 2 H), 7.18–7.14 (m, 1 H), 7.12 (dd, J₁= 5.0 Hz, J₂= 3.8 Hz, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 160.1, 139.3, 137.6,

130.8, 129.1, 128.6, 127.9, 124.7, 120.4 ppm. HRMS (ESI): calcd.

for C₁₁H₁₀NOS [M + H]⁺204.0483; found 204.0487.

Methyl 4-(2-{[2-(Methylthio)phenyl]carbamoyl}benzo[b]thiophen-3-

yl)benzoate (7c): Following the general procedure yielded the crude

product, which was purified by column chromatography on silica

gel (EtOAc/hexane, 20:80) to afford 7c (17 mg, 16% yield) as a pale

N-Phenylfuran-2-carboxamide (8d): Following the general pro-

cedure yielded the crude product, which was purified by column

chromatography on silica gel (EtOAc/hexane, =20:80) to afford 8d

(86 mg, 46% yield) as a pale orange solid; m.p. 113–115 °C. IR

yellow solid; m.p. 184–186 °C. IR (KBr): ν = 3400, 1579, 1271,

˜

1361, 757 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.63 (br. s, 1 H),

8.44 (dd, J₁= 8.3 Hz, J₂= 0.9 Hz, 1 H), 8.26 (d, J = 8.4 Hz, 2 H),

7.96 (d, J = 8.1 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.53–7.49 (m,

1 H), 7.46 (dd, J₁= 7.5 Hz, J₂= 0.6 Hz, 1 H), 7.42–7.40 (m, 1 H),

7.39–7.37 (m, 1 H), 7.32–7.28 (m, 1 H), 7.06 (td, J₁= 7.6 Hz, J₂=

1.4 Hz, 1 H), 4.00 (s, 3 H), 2.08 (s, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 166.6, 160.5, 140.2, 139.9, 138.4, 138.1, 136.5, 136.4,

133.1, 130.8, 130.7, 130.6, 128.8, 126.9, 125.4, 125.1, 124.7, 124.5,

122.6, 120.7, 52.4, 19.4 ppm. HRMS (ESI): calcd. for

C₂₄H₁₉NNaO₃S₂[M + Na]⁺456.0704; found 456.0703.

(KBr): ν = 3410, 1655, 1535, 1165, 754 cm^–1. ¹H NMR (400 MHz,

˜

CDCl₃): δ = 8.12 (br. s, 1 H), 7.68 (dd, J₁= 8.7 Hz, J₂= 1.1 Hz, 2

H), 7.54 (dd, J₁= 1.7 Hz, J₂= 0.7 Hz, 1 H), 7.41–7.37 (m, 2 H),

7.27 (dd, J₁= 3.5 Hz, J₂= 0.8 Hz, 1 H), 7.19–7.15 (m, 1 H), 6.59

(dd, J₁= 3.5 Hz, J₂= 1.8 Hz, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 156.1, 147.8, 144.2, 137.4, 129.1, 124.6, 119.9, 115.3,

112.7 ppm. HRMS (ESI): calcd. for C₁₁H₁₀NO₂[M + H]⁺

188.0712; found 188.0704.

3-(4-Acetylphenyl)-N-[2-(methylthio)phenyl]benzofuran-2-carbox-

amide (7d): Following the general procedure yielded the crude prod-

uct, which was purified by column chromatography on silica gel

(EtOAc/hexane, 20:80) to afford 7d (66 mg, 66% yield) as a yellow

5-(4-Acetylphenyl)-N-phenylfuran-2-carboxamide (10): Following

the general procedure yielded the crude product, which was puri-

fied by column chromatography on silica gel (EtOAc/hexane, 20:80)

to afford 10 (20 mg, 26% yield) as a colorless solid; m.p. 35–37 °C.

1

IR (KBr): ν = 3309, 2927, 1624, 1551, 1246, 713 cm^–1. H NMR

solid; m.p. 127–129 °C. IR (KBr): ν = 3434, 1676, 1510, 1266,

˜

1

750 cm^–1. H NMR (400 MHz, CDCl₃): δ = 8.89 (br. s, 1 H), 8.60

(400 MHz, CDCl₃): δ = 8.22 (br. s, 1 H), 8.04 (d, J = 8.6 Hz, 2 H),

7.85 (d, J = 8.6 Hz, 2 H), 7.72 (dd, J₁= 8.7 Hz, J₂= 1.1 Hz, 2 H),

7.41 (t, J = 8.4 Hz, 2 H), 7.36 (d, J = 3.6 Hz, 1 H), 7.20 (t, J =

7.4 Hz, 1 H), 6.94 (d, J = 3.6 Hz, 1 H), 2.65 (s, 3 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 197.3, 155.9, 154.5, 154.4, 147.7,

137.2, 136.7, 133.4, 129.2, 129.1, 124.8, 124.5, 120.2, 117.6, 109.9,

26.7 ppm. HRMS (ESI): calcd. for C₁₉H₁₆NO₃[M + H]⁺306.1130;

found 306.1139. This compound contains trace amounts of another

isomer.

(d, J = 8.1 Hz, 1 H), 8.14 (d, J = 8.6 Hz, 2 H), 8.07 (d, J = 8.7 Hz,

2 H), 8.02 (d, J = 7.3 Hz, 1 H), 7.62 (dd, J₁= 7.2 Hz, J₂= 0.8 Hz,

1 H), 7.51 (dd, J₁= 7.8 Hz, J₂= 1.2 Hz, 1 H), 7.46 (dd, J₁= 7.3 Hz,

J₂= 1.4 Hz, 1 H), 7.44–7.38 (m, 2 H), 7.15 (td, J₁= 7.6 Hz, J₂=

1.4 Hz, 1 H), 2.65 (s, 3 H), 2.23 (s, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 197.5, 161.8, 154.5, 154.1, 138.2, 137.6, 133.5, 133.2,

130.5, 129.0, 128.7, 128.6, 127.0, 126.1, 124.9, 124.3, 121.1, 120.6,

114.8, 111.7, 26.8, 19.2 ppm. HRMS (ESI): calcd. for C₂₄H₂₀NO₃S

[M + H]⁺402.1164; found 402.1164.

N-(Quinolin-8-yl)-3-[4-(trifluoromethyl)benzyl]thiophene-2-carb-

oxamide (12): Following the general procedure yielded the crude

product, which was purified by column chromatography on silica

gel (EtOAc/hexane, 15:85) to afford 12 (72 mg, 70% yield) as a

N-[2-(Dimethylamino)ethyl]thiophene-2-carboxamide (8a):^[33b]Fol-

lowing the general procedure yielded the crude product, which was

purified by column chromatography on silica gel (EtOAc/hexane,

20:80) to afford 8a (44 mg, 22% yield) as a yellow, thick liquid. IR

colorless solid; m.p. 107–109 °C. IR (KBr): ν = 3647, 1525, 1227,

˜

1

(KBr): ν = 3308, 2947, 1630, 1551, 718 cm^–1. H NMR (400 MHz,

754, 593 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.48 (br. s, 1 H),

8.87 (dd, J₁= 7.4 Hz, J₂= 1.5 Hz, 1 H), 8.79 (dd, J₁= 4.2 Hz, J₂

= 1.6 Hz, 1 H), 8.17 (dd, J₁= 8.3 Hz, J₂= 1.4 Hz, 1 H), 7.61–7.53

(m, 4 H), 7.46 (dd, J₁= 8.2 Hz, J₂= 3.9 Hz, 2 H), 7.41 (d, J =

5.1 Hz, 1 H), 6.92 (d, J = 5.1 Hz, 1 H), 4.60 (s, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 160.9, 148.3, 144.4, 138.5, 136.4,

134.5, 132.2, 131.4, 129.2, 128.6 (q, J_C,F= 32 Hz), 128.0, 127.6,

127.4, 125.5 (q, J_C,F= 3.8 Hz), 124.4 (q, J_C,F= 270.2 Hz), 121.9,

121.8, 120.3, 116.6, 30.1 ppm. HRMS (ESI): calcd. for

C₂₂H₁₆F₃N₂OS [M + H]⁺413.0935; found 413.0919.

˜

CDCl₃): δ = 7.54 (dd, J₁= 3.8 Hz, J₂= 1.2 Hz, 1 H), 7.46 (dd, J₁

= 5.0 Hz, J₂= 1.1 Hz, 1 H), 7.06 (dd, J₁= 5.0 Hz, J₂= 3.7 Hz, 1

H), 6.86 (br. s, 1 H), 3.50 (dd, J₁= 11.7 Hz, J₂= 5.6 Hz, 2 H), 2.50

(t, J = 6.0 Hz, 2 H), 2.26 (s, 6 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 162.0, 139.3, 129.8, 127.9, 127.5, 57.8, 45.2, 37.1 ppm.

HRMS (ESI): calcd. for C₉H₁₅N₂OS [M + H]⁺199.0905; found

199.0908.

N-[2-(Diethylamino)ethyl]thiophene-2-carboxamide (8b):^[33c]Follow-

ing the general procedure yielded the crude product, which was

purified by column chromatography on silica gel (EtOAc/hexane,

3-(4-Nitrobenzyl)-N-(quinolin-8-yl)thiophene-2-carboxamide (14):

20:80) to afford 8b (75 mg, 33% yield) as a brown, thick liquid. IR

Following the general procedure yielded the crude product, which

1

(KBr): ν = 3313, 2970, 1629, 1550, 718 cm^–1. H NMR (400 MHz, was purified by column chromatography on silica gel (EtOAc/hex-

˜

CDCl₃): δ = 7.51 (dd, J₁= 3.7 Hz, J₂= 1.1 Hz, 1 H), 7.38 (dd, J₁ane, 20:80) to afford 14 (82 mg, 85% yield) as a black solid; m.p.

= 5.0 Hz, J₂= 1.0 Hz, 1 H), 7.18 (br. s, 1 H), 7.00 (dd, J₁= 4.9 Hz,

J₂= 3.7 Hz, 1 H), 3.40 (dd, J₁= 11.4 Hz, J₂= 6.0 Hz, 2 H), 2.57

(t, J = 12.4 Hz, 2 H), 2.50 (q, J = 7.2, 4 H), 0.98 (t, J = 7.2 Hz, 6

150–152 °C. IR (KBr): ν = 3434, 1654, 1519, 1344, 762 cm^–1. ¹H

NMR (400 MHz, CDCl₃): δ = 10.48 (br. s, 1 H), 8.84–8.82 (m, 2

H), 8.21 (dd, J₁= 8.3 Hz, J₂= 1.6 Hz, 1 H), 8.16 (d, J = 8.8 Hz,

˜

3738

www.eurjoc.org

Eur. J. Org. Chem. 2015, 3727–3742

Arylation and Alkylation of Thiophene- and Furan-2-carboxamides

2 H), 7.62–7.56 (m, 2 H), 7.52–7.48 (m, 3 H), 7.46 (d, J = 5.1 Hz, (100 MHz, CDCl₃): δ = 161.3, 148.2, 146.4, 138.6, 136.3, 134.8,

1 H), 6.95 (d, J = 5.1 Hz, 1 H), 4.63 (s, 2 H) ppm. ¹³C NMR 132.5, 131.2, 128.0, 127.8, 127.4, 121.7, 121.6, 116.6, 31.9, 30.9,

(100 MHz, CDCl₃): δ = 160.8, 148.4, 148.1, 146.5, 143.8, 138.5, 30.0, 29.7, 29.5, 29.3, 22.7, 14.2 ppm. HRMS (ESI): calcd. for

136.4, 134.4, 132.2, 131.3, 129.6, 128.0, 127.7, 127.4, 123.8, 122.0,

121.8, 116.6, 35.0 ppm. HRMS (ESI): calcd. for C₂₁H₁₆N₃O₃S [M

+ H]⁺390.0912; found 390.0926.

C₂₂H₂₇N₂OS [M + H]⁺367.1844; found 367.1851.

Ethyl 2-[2-(Quinolin-8-ylcarbamoyl)thiophen-3-yl]acetate (16e): Fol-

lowing the general procedure yielded the crude product, which was

purified by column chromatography on neutral alumina (EtOAc/

hexane, 20:80) to afford 16e (37 mg, 43% yield) as a colorless solid;

3-Butyl-N-(quinolin-8-yl)thiophene-2-carboxamide (16a): Following

the general procedure yielded the crude product, which was puri-

fied by column chromatography on silica gel (EtOAc/hexane, 10:90)

to afford 16a (50 mg, 65% yield) as a colorless solid; m.p. 57–59 °C.

m.p. 143–145 °C. IR (KBr): ν = 3331, 1659, 1525, 1421, 1327,

˜

786 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.48 (br. s, 1 H), 8.85

IR (KBr): ν = 3356, 2927, 1679, 1525, 728 cm^–^{1 1}H NMR

.

(dd, J₁= 4.2 Hz, J₂= 1.6 Hz, 1 H), 8.83 (dd, J₁= 7.0 Hz, J₂

=

˜

2.1 Hz, 1 H), 8.20 (dd, J₁= 8.3 Hz, J₂= 1.6 Hz, 1 H), 7.61–7.54

(m, 2 H), 7.49 (dd, J₁= 8.3 Hz, J₂= 4.2 Hz, 1 H), 7.46 (d, J =

5.0 Hz, 1 H), 7.13 (d, J = 5.0 Hz, 1 H), 4.25–4.19 (m, 4 H), 1.27

(t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 170.9,

160.8, 148.4, 138.7, 138.6, 136.4, 134.5, 133.0, 131.6, 128.0, 127.4,

127.1, 121.8, 121.7, 116.7, 61.0, 35.0, 14.2 ppm. HRMS (ESI):

calcd. for C₁₈H₁₇N₂O₃S [M + H]⁺341.0960; found 341.0966.

(400 MHz, CDCl₃): δ = 10.46 (br. s, 1 H), 8.89 (dd, J₁= 7.5 Hz,

J₂= 1.3 Hz, 1 H), 8.82 (d, J = 4.2 Hz, 1 H), 8.16 (dd, J₁= 8.3 Hz,

J₂= 1.0 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.52 (d, J = 8.2 Hz, 1

H), 7.45 (dd, J₁= 8.2 Hz, J₂= 4.2 Hz, 1 H), 7.41 (d, J = 5.0 Hz,

1 H), 7.03 (d, J = 5.0 Hz, 1 H), 3.15 (t, J = 8.0 Hz, 2 H), 1.83–1.75

(m, 2 H), 1.54–1.46 (m, 2 H), 1.00 (t, J = 7.4 Hz, 3 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 161.3, 148.2, 146.4, 138.6, 136.4,

134.7, 132.5, 131.2, 128.0, 127.8, 127.4, 121.7, 121.6, 116.6, 33.1,

29.8, 22.8, 14.1 ppm. HRMS (ESI): calcd. for C₁₈H₁₉N₂OS [M +

H]⁺311.1218; found 311.1202.

Supporting Information (see footnote on the first page of this arti-

cle): X-ray crystal structures of compounds 3e, 5a, and 6a as well

as NMR spectra.

3-Heptyl-N-(quinolin-8-yl)thiophene-2-carboxamide (16b): Follow-

ing the general procedure yielded the crude product, which was

purified by column chromatography on silica gel (EtOAc/hexane,

Acknowledgments

10:90) to afford 16b (68 mg, 77% yield) as a brown solid; m.p. 68–

This work was funded by the Indian Institute of Science Education

and Research (IISER), Mohali. The authors thank IISER Mohali

for the use of the NMR, X-ray, and HRMS facilities. The authors

also thank the Department of Chemical Sciences of IISER Mohali

for providing access to the single-crystal X-ray facility. R. P. thanks

IISER Mohali for providing a project assistant fellowship. B. G.

thanks the Department of Science and Technology (DST), New

Delhi for providing an INSPIRE SRF fellowship. R. S. and R. P.

thank the Council of Scientific and Industrial Research, University

Grants Commitee (CSIR-UGC), New Delhi for providing the JRF

and SRF fellowships, respectively.

1

69 °C. IR (KBr): ν = 3440, 2923, 1650, 1525, 1217 cm^–1. H NMR

˜

(400 MHz, CDCl₃): δ = 10.46 (br. s, 1 H), 8.89 (dd, J₁= 7.5 Hz,

J₂= 1.4 Hz, 1 H), 8.81 (d, J = 4.2 Hz, 1 H), 8.16 (d, J = 8.2 Hz, 1

H), 7.59–7.50 (m, 2 H), 7.45 (dd, J₁= 8.2 Hz, J₂= 4.2 Hz, 1 H),

7.41 (d, J = 5.0 Hz, 1 H), 7.03 (d, J = 5.0 Hz, 1 H), 3.14 (t, J =

7.9 Hz, 2 H), 1.83–1.76 (m, 2 H), 1.51–1.44 (m, 2 H), 1.40–1.25 (m,

6 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 161.2, 148.2, 146.4, 138.6, 136.3, 134.7, 132.5, 131.2, 128.0,

127.8, 127.4, 121.7, 121.6, 116.6, 31.9, 30.9, 30.0, 29.7, 29.2, 22.7,

14.2 ppm. HRMS (ESI): calcd. for C₂₁H₂₅N₂OS [M + H]⁺

353.1688; found 353.1688.

3-(3-Chloropropyl)-N-(quinolin-8-yl)thiophene-2-carboxamide (16c):

Following the general procedure yielded the crude product, which

was purified by column chromatography on silica gel (EtOAc/hex-

ane, 10:90) to afford 16c (37 mg, 45% yield) as a colorless solid;

[1] For selected reviews and articles that reveal the bioactivity and

other applications of thiophenes and furans, see: a) J. Roncali,

Chem. Rev. 1992, 92, 711; b) K. Masui, A. Mori, K. Okano,

K. Takamura, M. Kinoshita, T. Ikeda, Org. Lett. 2004, 6, 2011;

c) K. Kobayashi, M. S. M. Ahmed, A. Mori, Tetrahedron 2006,

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m.p. 102–104 °C. IR (KBr): ν = 3357, 2922, 1656, 1526, 763 cm^–1.

˜

¹H NMR (400 MHz, CDCl₃): δ = 10.45 (br. s, 1 H), 8.86–8.83 (m,

2 H), 8.19 (dd, J₁= 8.3 Hz, J₂= 1.6 Hz, 1 H), 7.60–7.53 (m, 2 H),

7.48 (dd, J₁= 8.3 Hz, J₂= 4.2 Hz, 1 H), 7.44 (d, J = 5.0 Hz, 1 H),

7.07 (d, J = 5.0 Hz, 1 H), 3.66 (t, J = 6.6 Hz, 2 H), 3.30 (t, J =

7.5 Hz, 2 H), 2.32–2.25 (m, 2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 161.0, 148.4, 145.3, 138.6, 136.4, 134.6, 132.3, 131.3,

128.0, 127.7, 127.4, 121.8, 116.5, 44.5, 33.4, 27.0 ppm. HRMS

(ESI): calcd. for C₁₇H₁₆ClN₂OS [M + H]⁺331.0672; found

331.0674.

3-Octyl-N-(quinolin-8-yl)thiophene-2-carboxamide (16d): Following

the general procedure yielded the crude product, which was puri-

fied by column chromatography on silica gel (EtOAc/hexane, 10:90)

to afford 16d (86 mg, 94% yield) as a pale brown solid; m.p. 68–

1

70 °C. IR (KBr): ν = 3359, 2924, 1658, 1525, 789 cm^–1. H NMR

˜

(400 MHz, CDCl₃): δ = 10.47 (br. s, 1 H), 8.89 (dd, J₁= 7.5 Hz,

J₂= 1.4 Hz, 1 H), 8.81 (dd, J₁= 4.2 Hz, J₂= 1.6 Hz, 1 H), 8.16

(dd, J₁= 8.3 Hz, J₂= 1.6 Hz, 1 H), 7.58 (t, J = 8.1 Hz, 1 H), 7.52

(dd, J₁= 8.3 Hz, J₂= 1.4 Hz, 1 H), 7.46 (dd, J₁= 8.2 Hz, J₂

=

4.2 Hz, 1 H), 7.42 (d, J = 5.0 Hz, 1 H), 7.03 (d, J = 5.0 Hz, 1 H),

3.14 (t, J = 7.9 Hz, 2 H), 1.83–1.76 (m, 2 H), 1.49–1.44 (m, 2 H),

1.38–1.23 (m, 8 H), 0.88 (t, J = 6.7 Hz, 3 H) ppm. ¹³C NMR

Eur. J. Org. Chem. 2015, 3727–3742

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3739

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J. Org. Chem. 2013, 78, 11911; l) R. Parella, S. A. Babu, Synlett

2014, 25, 1395; m) R. Parella, S. A. Babu, J. Org. Chem. 2015,

80, 2339, and references cited therein.

For an example of the C-3 arylation of thiophene-2-carboxam-

ide that is directed by 8-aminoquinoline in the presence of an

iron catalyst with an aryl borate reagent [derived from Ph-Bpin

and BuLi], see: R. Shang, L. Ilies, S. Asako, E. Nakamura, J.

Am. Chem. Soc. 2014, 136, 14349.

For selected papers on the C–H functionalization of the C-3

position of thiophene by using coupling partners other than

aryl or alkyl reagents, see: a) M. Nishino, K. Hirano, T. Satoh,

M. Miura, Angew. Chem. Int. Ed. 2013, 52, 4457; b) R. Odani,

M. Nishino, K. Hirano, T. Satoh, M. Miura, Heterocycles

2014, 88, 595.

[17]

[18]

[26]

[27]

[19]

[20]

For an article on selective arylation at the C-3 position of a 2-

substituted thiophene by using phenyl triflate, see: T. Okazawa,

T. Satoh, M. Miura, M. Nomura, J. Am. Chem. Soc. 2002, 124,

5286, this reaction afforded the C-3-arylated thiophenecarbox-

amide (71%) along with a double arylated (C-3 and C-5) thio-

phenecarboxamide (8%).

For papers on the selective arylation at the C-4 position of 2-

and/or 3-substituted thiophenes by using boronic acids, see: a)

S. Kirchberg, S. Tani, K. Ueda, J. Yamaguchi, A. Studer, K.

Itami, Angew. Chem. Int. Ed. 2011, 50, 2387, and references

cited therein; b) K. Yamaguchi, J. Yamaguchi, A. Studer, K.

[28]

[29]

For an example of the C-3 allylation of thiophene-2-carbox-

amide with allyl phenyl ether directed by 8-aminoquinoline in

the presence of an iron catalyst, see: S. Asako, L. Ilies, E. Naka-

mura, J. Am. Chem. Soc. 2013, 135, 17755.

For an example of the C-3 alkylation of thiophene-2-carbox-

amide with an alkyl tosylate directed by 8-aminoquinoline in

the presence of an iron catalyst, see: L. Ilies, T. Matsubara, S.

Ichikawa, S. Asako, E. Nakamura, J. Am. Chem. Soc. 2014,

136, 13126.

Eur. J. Org. Chem. 2015, 3727–3742

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S. A. Babu et al.

FULL PAPER

[30] a) For an example involving the C-3 alkynylation of thiophene-

2-carboxamide with an alkyne reagent directed by 8-amino-

quinoline in the presence of a palladium catalyst, see: Y. Ano,

M. Tobisu, N. Chatani, Org. Lett. 2012, 14, 354; b) for an ex-

ample of the C-5 alkylation of thiophene-4-carboxamide with

butyl bromide directed by 8-aminoquinoline in the presence of

a nickel catalyst, see: Y. Aihara, N. Chatani, J. Am. Chem. Soc.

2013, 135, 5308.

[31] For an example of the C-3 silylation/germanylation of thio-

phene-2-carboxamide directed by 8-aminoquinoline in the

presence of a palladium catalyst, see: K. S. Kanyiva, Y. Kuni-

nobu, M. Kanai, Org. Lett. 2014, 16, 1968.

[32] The Pd-catalyzed C-3–H arylation reactions of substrate 1a

with the corresponding heteroaryl halides that contained more

than one halo substituent gave products 3e (49% yield) and 3f

(53% yield) in moderate yields. Although we are unable to pro-

vide a clear explanation for this, a plausible reason for the

moderate yields in these cases may be attributed to the reactiv-

ity pattern or the extent of assistance provided by the bidentate

ligand [i.e., 2-(methylthio)aniline] that is incorporated into sub-

strate 1a. Similar types of products 5c (73% yield) and 5d (62%

yield) were obtained in relatively good yields from substrate 1c,

which was derived from the bidentate ligand 8-aminoquinoline.

This reasoning may also be attributed to the low yields of prod-

ucts 4a–4c (yield up to 40%) from substrate 1b, which was pre-

pared from the 2-(methylthio)aniline. Substrate 1d, which was

derived from 8-aminoquinoline, gave products 6a–6h in rela-

tively good yields (yield up to 67%). These results indicate that

the bidentate ligand 8-aminoquinoline assisted the C-3–H aryl-

ation of the furan and thiophene derivatives more effectively

than the bidentate ligand 2-(methylthio)aniline. Apart from

this discussion, we cannot ignore that the low yields of prod-

ucts 3d–3f, 4a–4c, and 6d–6f also may be a result of the reactiv-

ity of the corresponding aryl halides or heteroaryl halides,

which contained more than one substituents [e.g., Cl and F or

the O-CH₂–CH₂–O unit].

[33] a) D. S. Goldfarb, US 20090163545 A1, 2009; b) Olsson, H. C.

Hansen, C.-M. Andersson, Tetrahedron Lett. 2000, 41, 7947; c)

T. Kametani, T. Katagi, T. Fujiwara, Y. Akasawa, Yakugaku

Kenkyu 1954, 26, 544; d) CCDC-1048619 (for 3a), -1048620

(for 5a), and -1048621 (for 6a) contain the supplementary crys-

tallographic data for this paper. These data can be obtained

free of charge from The Cambridge Crystallographic Data

Centre via www.ccdc.cam.ac.uk/data_request/cif.

Received: February 20, 2015

Published Online: April 30, 2015

3742

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Eur. J. Org. Chem. 2015, 3727–3742

Article Doi

Pd(OAc)2/AgOAc catalytic system based bidentate ligand directed regiocontrolled C-H arylation and alkylation of the C-3 position of thiophene- and furan-2-carboxamides

DOI: 10.1002/ejoc.201500249

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Article abstract of DOI:10.1002/ejoc.201500249

Full text of DOI:10.1002/ejoc.201500249

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