Pd-Catalyzed Oxidative Aminocarbonylation of Arylboronic Acids with Unreactive Tertiary Amines via C-N Bond Activation

Yuvraj A. Kolekar and Bhalchandra M. Bhanage*

Article

Pd-Catalyzed Oxidative Aminocarbonylation of Arylboronic Acids

with Unreactive Tertiary Amines via C−N Bond Activation

Cite This: https://doi.org/10.1021/acs.joc.1c00345

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sı Supporting Information

ABSTRACT: An eﬃcient synthesis of tertiary amides from aryl

boronic acids and inert tertiary amines through the oxidative

carbonylation via C(sp )−N bond activation is presented. This

protocol signiﬁcantly restricts the homocoupling biarylketone

product. It involves the use of a homogeneous PdCl /CuI catalyst

and a heterogeneous Pd/C based catalyst, which promotes

C(sp )−N bond activation of tertiary amines with aryl boronic

acids. This process represents a ligand-free, base-free, and

recyclable catalyst along with an ideal oxidant like molecular

oxygen.

INTRODUCTION

Tertiary amide and its derivatives are crucial functional motifs

in natural products, pharmaceuticals, agrochemicals, adhesives,

Scheme 1. Various Strategies of Aminocarbonylation for

Tertiary Amides Synthesis

■

and biologically active compounds. Because of their stability

and importance, a simple oxidative amidations strategy is used

for the synthesis of amides by using a readily available

precursor to valuable products. Conventionally, amides are

synthesized by condensation reaction between amines and acid

derivatives. However, direct oxidative amidations of various

starting materials such as benzaldehyde, benzyl alcohols, and

carbamoyl chlorides with amines has been studied. Con-

versions such as transamidation of tertiary amides with

nitrobenzene opens up newer avenues for derivatization of

tertiary amides under reductive conditions and amidations of

thioacids with azides as well as aminolysis of aryl esters.

Although they have the potential utility of desired products,

these strategies show some drawbacks, such as requirements of

the stoichiometric amount of base, use of explosive and toxic

oxidants (TBHP, hydrogen peroxide), and hazardous reagents.

Over the past decades, the transition-metal-catalyzed oxidative

carbonylation reaction gives a general and resourceful method

More recently, Ren et al. developed oxidative carbonylative

tertiary amide from arylboronic acids and secondary amines as

a starting material (Scheme 1a). The Kristensen group

achieves amide synthesis from organoboronates with carba-

5b,c

moyl chloride counterparts (Scheme 1b).

But the current

for building carbonyl compounds. Palladium-catalyzed amino-

protocols have limitations. It required a longer reaction time to

convert the desired products, high CO pressure, a narrow

substrate scope and low yield with aliphatic secondary amines.

However, because of their low nucleophilicity, aryl boronic

acids as nucleophiles and activation of inert C−N bonds that

carbonylation of aryl halides, aryl triﬂates, or aryl tosylates

with primary or secondary amines represents an eﬀective

method for the development of amides.

Organoboronic acids are stable, commercially available, and

environmentally benign feedstocks as coupling partners in

transition-metal-catalyzed Suzuki−Miyaura cross-couplings

Special Issue: Enabling Techniques for Organic Syn-

thesis

that are widely used in the recent organic transformation.

In the past few decades, Wu’s group also reports an amide

synthesis by using N-chloroamines formed in situ with NCS

Received: February 11, 2021

and under high CO pressure (Scheme 1a). Recently, Szostak

and co-workers also reported Pd-catalyzed synthesis of amides

by oxidative aminocarbonylation of arylsilanes (Scheme 1a).

XXXX American Chemical Society

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

require high dissociation energy and site-selective functional-

ization make this process challenging to activate in oxidative

carbonylation reactions. Tertiary amines are typical byproducts

in synthetic chemistry, pharmaceuticals, and agrochemicals

industries, which require exploration in organic syntheses

through cleaving of C−N bonds into relevant fragments and

Table 1. Screening Eﬀect of Catalyst, Catalyst Loading, and

Ligands

transform into valuable organic compounds. Scientiﬁcally,

the activation of the inert C−N bond of the tertiary amine is a

big challenge because of their lower binding aﬃnity with

transition metals and high dissociation energy. To the best of

our knowledge, the oxidative aminocarbonylation of arylbor-

onic acids with an inert tertiary amine via C−N bond

activation to transform the desired tertiary amide products is

not yet reported.

yield (%)

entry

catalyst

PdCl (PPh

Pd(OAc)

Pd(dba)

ligand

trace

)

PPh

PdCl

Our previously reported amide synthesis through sp C−N

P(t-Bu)

PCy

bond activation of tertiary amines worked well, but not for

arylboronic acids. Taking inspiration from the sp C−N bond

Xantphos

SPhos

dppf

dppp

dppe

activation of inert tertiary amines, we envisioned that oxidative

aminocarbonylation with an aryl boronic acid as the

nucleophile could be synthesized by introducing CO between

two reactants for C−C bond and C−N bond formation

^P^d^C^l2

dppm

(

Scheme 1c). Herein, we report for the ﬁrst time oxidative

carbonylation of aryl boronic acids and inert tertiary amines as

an in situ aminal source that provides access to a series of aryl

and heteroaryl amides in good yields. Palladium-catalyzed

activation of the C−N bond in inert tertiary amines has been

established to convenient nitrogen and carbon sources to build

valuable molecules.

^P^d^C^l2

Reaction conditions: ArB(OH) (0.75 mmol), Et N (1 mmol), Pd

catalyst (1 mol %), CuBr (5 mol %), 8 atm of CO/O (7:1) in a 10

mL of DMSO, 100 °C, 12 h. Yields were detected by GC and GC−

MS.

Table 2. Optimization of Reaction Parameters for

Aminocarbonylation Reaction

RESULT AND DISCUSSION

Our initial studies focused on achieving N-dealkylative

■

carbonylation of the Et N (2a) with phenylboronic acid

(

1a). We observed that the desired product was formed under

the combined reaction conditions of [PdCl (PPh ) ] and PPh

3 2

in a dry DMSO at 100 °C for 12 h under 8 bar CO/O (7:1)

yield (%)

pressure (Table 1, entry 1). (Note: The CO/O is an explosive

under certain condition.) Under these reaction conditions,

only 45% yield of 3a was obtained along with 26% of

benzophenone as a homocoupling product. Increasing the

yield of the desired amide instead of a homocoupling product

is diﬃcult under this condition. Encouraged by rudimentary

results, we performed a set of experiments to get a better yield

of the reaction. At ﬁrst, we examined various palladium

entry

solvent

DMSO

temp

Cu(OAc)₂

CuCl₂

CuO

100

trace

17(12)

trace

DMSO

DMF

Cu O

CuCl

CuBr

CuI

precatalysts and PPh as a ligand that resulted in a lower yield

of 3a (Table 1, entries 2−4). Moreover, the ligand’s role

aﬀords more possibility for Pd catalysts by deviously varying

the electronic property of the catalytic center. We observed

that the bulky, electron-rich bidentate ligands were most

eﬃcient from the literature survey due to their large bite

NaI

TBAI

CuI

THF

angle. Unfortunately, these ligands also failed to give the

resultant amide in good yield compared to homocoupling

anisole

1,4 dioxane

MeCN

toluene

MeCN

product (Table 1, entries 5−12). It was observed that PdCl

was the best catalyst without any ligand (Table 1, entry 13).

Compared to the previously reported methodologies,

oxidants are required, such as 3 equiv of CuO, TBHP, O ,

55(38)

77(88)

6b,19

and air, to activate the C−N bond of tertiary amines.

Subsequently, diﬀerent copper co-catalysts were tested, such as

CuCl, CuCl , Cu(OAc) , CuO, Cu O, CuBr, and CuI, with

Reaction conditions: ArB(OH)₂(0.75 mmol), Et N (1 mmol),

PdCl

catalyst (1 mol %), Cu (5 mol %), solvent (10 mL), 8 atm of

molecular oxygen as an oxidant (Table 2, entry 7). To our

delight, the byproduct 4a was suppressed when we carried out

the reaction in the presence of CuI as a co-catalyst. CuI (5 mol

CO/O (7:1), 100 °C, 12 h. Yields were detected by GC and GC−

MS. 2 atm of CO/O (3:1). H O (8 equiv) instead oxidant O .

2 2 2

120 °C instead of 100 °C. 18 h instead of 12 h. ND - not detected.

) was realized to be superior and capable of ensuring high

conversion rates and yields. However, we thought that a halide

J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

promoter could enhance the reaction yield. Subsequently, we

also study the eﬀect of iodine promoters such as KI, NaI, and

TBAI without CuI. Unfortunately, it failed to improve the

desired product yield (Table 2, entries 8−10). Worth noticing,

eﬀect on the desired yield 3a, whereas, at decreasing the

reaction time, the yield was decreased.

Under the optimal reaction condition, we explored the

substrate scope of aryl and heteroaryl boronic acids with N-

PdCl and CuI are crucial for the reaction as the absence of

dealkylative/carbonylation of Et N. As shown in Scheme 2, the

either one failed to yield the amide product. Next, various

solvents were studied. Acetonitrile was shown to be the most

eﬀective compared to DMSO, THF, DMF, and toluene, and

the byproduct 4a was completely suppressed (Table 2, entry

aryl boronic acids bearing electron-donating methyl and

methoxy substituents at the o- and p- positions to the phenyl

ring aﬀorded the tertiary amide products in good yield. Next,

the 2-naphthylboronic acid also aﬀords good yield with this

practice. Electron-withdrawing substituents such as halides,

5). Further, we examined the CO pressure eﬀect, and 2 atm

−

CF , −NO , and −CN on the phenyl ring also provide a

of CO/O (3:1) could be highly eﬃcient to aﬀord the desired

good yield of the respective products. Moreover, biological as

well as pharmaceutical relevant heteroaryl boronic acids are

eﬀectively applied in this protocol, aﬀording 66%, 67%, 60%,

and 62% yield of 3l, 3m, 3x, and 3y, respectively. Satisfactorily,

the aryl boronic acid bearing electron-withdrawing and

electron-donating groups performed successfully under the

standard conditions.

After evaluating the aryl boronic acid substrate scope, we

turned to extend the scope for diﬀerent tertiary amines with

phenylboronic acid under the optimized condition. These

results are summarized in Scheme 3. Remarkably, symmetrical

aliphatic, alicyclic, and aryl tertiary amines were well tolerated

and aﬀord the corresponding amides in good yields.

amide in 87% (Table 2, entry 15), while decreasing the CO/

O ratio, yield of desired amide also decreased (Table 2). In

the presence of air as an oxidant instead of O , the respective

yield of 3a was reduced (Table 2, entry 17). Later, we

performed a reaction in H O (1 equiv) instead of oxidant O ;

the obtained yield of 3a was much lower. Further, we carried

out a reaction in 5 equiv of H O to give 55% yield of 3a, but

increasing the concentration of water in the reaction decreases

the yield of 3a (Table 2, entry 18).

Notably, the desired product yield decreases when the

reaction was performed at 90 °C and there was no signiﬁcant

change observed after increasing the reaction temperature to

20 °C (Table 2, entry 19). Finally, we studied the reaction

time; at increasing the reaction time, there is no remarkable

Scheme 3. Scope of Aminocarbonylation of Phenylboronic

Acid with Various Tertiary Amines

a,b

Scheme 2. Scope of Aminocarbonylation of ArB(OH) with

a,b

Et N as an Amine Source

Reaction conditions: ArB(OH)₂(0.75 mmol), Et N (1 mmol),

PdCl (1 mol %), CuI (5 mol %) in 10 mL of MeCN under 2 atm of

CO/O (3:1) pressure at 100 °C for 12 h. Isolated yield.

It was found that symmetrical tertiary amines performed well

under the optimal reaction condition to give corresponding

amide products 3n, 3o, 3p, 3q, and 3r, in good yield. Notably,

the selectivity of N-dealkylation of symmetrical stable tertiary

amines was not dependent on alkyl chain lengths and was well

tolerated under corresponding tertiary amides in excellent

Reaction conditions: ArB(OH)₂(0.75 mmol), Et N (1 mmol),

PdCl (1 mol %, 1.3 mg), CuI (5 mol %, 7.1 mg) in 10 mL of MeCN

under 2 atm of CO/O (3:1) pressure at 100 °C for 12 h. Isolated

yield. The reaction was scaled up to 5 mmol (86.3 mg, 65% yield).

J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

yields. Outstandingly, the N,N-dimethyl benzylamine and N,N-

diethyl aniline were also tested and aﬀorded good yield.

To our delight, the cyclic tertiary amines such as N-ethyl and

N-methyl derivatives all exhibited good compatibility in this

reaction. Further, the Pd/C catalyst and CuI were also

investigated for this transformation. On the basis of the results

pertaining to the heterogeneous catalytic system (Pd/C), the

yields are highly promising in the case of a homogeneous

catalytic system. Pd/C catalyst could be reused up to ﬁ ve times

with a slight decrease in its catalytic activity (Supporting

Information (SI), page S3).

On the basis of earlier reports and our own experimental

results, a plausible mechanism is anticipated (Scheme 5).

Initially, oxidative addition of ArB(OH) (1a) to the Pd(II)

catalyst, followed by CO insertion, gives acyl palladium

intermediate (I). Subsequently, intermediate (I) reacts with

secondary amine which is in situ generated from tertiary amine

(

Path C). Tertiary amines in the presence of CuI/O could

slowly release secondary amine (V) and aldehyde through the

formation of iminium-type intermediate (IV), followed by

b,16c,20,24

hydrolysis.

III) aﬀords the amide 3a product, and generated Pd(0)

species could be reoxidized by Cu/O to give Pd(II) continues

On the other hand, in Path B, the

transmetalation of complex (I) with 1a aﬀords the Pd-complex

II); further reductive elimination gives biaryl ketone 4a, and

generated Pd(0) species reoxidized to Pd(II) for the next

Further reductive elimination of complex

(

Further, to demonstrate the potential application of the

highly eﬃcient catalytic system, a gram scaled reaction was

carried out. Delightfully, the reaction of phenylboronic acid

could proceed smoothly, aﬀording 3a in 65% yield. (Scheme 4)

19a,21

the cycle (Path A).

(

Scheme 4. Gram Scale Experiment

9a,21,22

cycle.

CONCLUSION

■

In summary, we have established the ﬁrst protocol for oxidative

aminocarbonylation of aryl boronic acids as an aryl source with

unreactive tertiary amines through C(sp )−N bond activation.

To gain some insights into the reaction mechanism, we carry

out some control experiments (SI, page S4). Initially, we

performed the reaction in the absence of oxygen, which

aﬀorded 70% yield of 3a, and without CuI, only a 50% yield of

By employing this method, eﬃcient syntheses of tertiary

aromatic amides were successfully accomplished, and the key is

that copper plays a dual role as a aryl boronic acid activator as

well as C(sp )−N bond cleavage of unreactive tertiary amines

a was observed. Notably, when we conduct the reaction in the

in the presence of molecular oxygen. To our delight, the

developed new method is highly eﬃcient for accessing the aryl

as well as heteroaryl amides, which are challenging to produce

with additional advantages such as low catalyst loading,

moisture sensitive, ligand-free, and base-free using oxygen as

an ideal oxidant.

absence of Et N, 70% of biaryl ketone was observed along with

9% of 1,1-biphenyl product formed. Further, we perform a

reaction in the absence of PdCl catalyst; selectively, 1,1-

biphenyl was observed. These results demonstrate that PdCl₂

and CuI are crucial for the reaction as the absence of either one

failed to yield amide product.

Scheme 5. Possible Reaction Mechanism

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

H), 1.08 (s, 6H). ¹³C { H} NMR (101 MHz, CDCl ) δ 171.0, 160.1,

EXPERIMENTAL SECTION

■

29.3, 128.0, 113.5, 55.1, 43.0, 39.4, 13.4.

N,N-Diethyl-2-naphthamide (3e).

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

v/v) mixture as eluent; isolated yield 77% (131 mg). H NMR (400

General Information. The chemicals were purchased from

Sigma-Aldrich and used without puriﬁcation. All the reaction

performances were examined by using GC−MS, TLC, and GC

techniques. The obtained products were puriﬁed by column

chromatography on silica gel. The H and C NMR spectra of

isolated products were recorded in CDCl on an Agilent at 400 MHz.

16c

Colorless oil; isolated

MHz, CDCl ) δ 7.91−7.70 (m, 4H), 7.54−7.35 (m, 3H), 3.56 (s,

H), 3.24 (s, 2H), 1.34−1.06 (m, 6H). C { H} NMR (101 MHz,

CDCl ) δ 171.3, 134.4, 133.3, 132.7, 128.2, 128.2, 127.7, 126.7, 126.6,

Spectral data are reported in ppm (δ) relative to tetramethylsilane

25.7, 123.8, 43.4, 39.4, 14.1, 12.9.

-Fluoro-N,N-diethyl-benzamide (3f).

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

v/v) mixture as eluent; isolated yield 72% (105.3 mg). H NMR (400

MHz, CDCl ) δ 7.32−7.20 (dd, 2H), 6.95 (dd, 2H), 3.40 (s, 2H),

.14 (s, 2H), 1.08 (s, 3H), 1.03 (s, 3H). C { H} NMR (101 MHz,

CDCl ): (ppm) 170.1, 164 (C-F, J = 247 Hz), 161.6 (C-F, J =

(

TMS) as an internal standard. The J values are shown in hertz, and

splitting patterns of the proton are described as s (singlet), d

doublet), t (triplet), and m (multiplet). All optimal reactions were

carried out under a 2 atm of CO/O (3:1) in the high-pressure

autoclave.

General Experimental Procedure for Oxidative Amino-

carbonylation of Aryl Boronic Acid with Tertiary Amines.

Aryl boronic acid (0.75 mmol, 1 equiv), tertiary amine (1 mmol, 1.3

16c

Colorless oil; isolated

(

C‑F

47 Hz), 133.2 (C-F, J = 8 Hz), 128.3, 115.3 (C-F, J = 22 Hz),

C‑F C‑F

15 (C-F, J = 22 Hz), 43.1, 39.2, 13.8, 12.7.

-Bromo-N,N-diethylbenzamide (3g).

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

v/v) mixture as eluent; isolated yield 75% (143.4 mg). H NMR (400

MHz, CDCl ) δ 7.44 (d, 2H), 7.17 (d, 2H), 3.44 (s, 2H), 3.15 (s,

2H), 1.13 (t, 3H), 1.02 (s, 3H). C { H} NMR (101 MHz, CDCl )

δ169.9, 136.0, 131.4, 127.9, 123.1, 43.2, 39.2, 13.4.

N,N-Diethyl-2-nitrobenzamide (3h).

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

v/v) mixture as eluent; isolated yield 65% (108.2 mg). H NMR (400

MHz, CDCl ) δ 8.12 (d, 1H), 7.64 (t, 1H), 7.49 (t, 1H), 7.33 (d,

H), 3.53 (q, 2H), 3.07 (q, 2H), 1.24 (t, 3H), 1.00 (t, 3H). C { H}

C‑F

equiv), PdCl (1 mol %, 1.3 mg), and CuI (5 mol %, 7.14 mg) in 10

16c

Colorless oil; isolated

mL of CH CN were added to a 100 mL stainless steel reactor. Then

the reactor was closed tightly and pressurized with 2 atm of CO/O₂

with the ratio of 3:1 at room temperature. (Note: The reactor was

pressurized with O , followed by CO. The CO/O is an explosive under

certain conditions.) Then, the reaction mixture was heated at 100 °C

electrical ceramic heater) and stirred with a mechanical stirrer for 12

h. After reaction completion, the autoclave was cooled to room

temperature and the remaining CO was degassed carefully. The

reaction mixture was diluted with ethyl acetate (10 mL) and extracted

with the aqueous solution, and the combined organic layer was dried

(

16c

Yellow oil; isolated

^o^v^e^r^N^a^S^O4 and concentrated under vacuum. The residue was

NMR (101 MHz, CDCl ) δ 167.1, 134.2, 133.5, 129.4, 127.9, 124.6,

puriﬁed by column chromatography on silica gel, and the obtained

pure product was conﬁrmed by GC, GC−MS, and NMR techniques.

The products were analyzed by GC−MS and IR. HRMS was recorded

on a micromass ESI TOF (time-of-ﬂight) mass spectrometer.

General Procedure of Gram Scale Study. Phenylboronic acid

2.7, 38.9, 13.48, 11.9.

N,N-Diethyl-4-nitrobenzamide (3i). Yellow oil; isolated through

0−200 mesh silica gel using pet ether:ethyl acetate (70:30 v/v)

mixture as eluent; isolated yield 67% (111.5 mg). H NMR (400

MHz, CDCl δ 8.25 (d, 2H), 7.56−7.49 (m, 2H), 3.55 (q, 2H), 3.19

(

5 × 0.75 mmol, 0.45 g), Et N (5.0 mmol, 0.50 g, 1.3 equiv), PdCl

(q, 2H), 1.24−1.10 (t, 6H). C { H} NMR (101 MHz, CDCl ) δ

(

5 mol %, 0.0088 g), and CuI (15 mol %, 0.028 g) in 10 mL of

68.8, 148.0, 143.3, 127.3, 123.8, 43.2, 39.4, 14.1, 12.8.

N,N-Diethyl-4-(triﬂuoromethyl)benzamide (3j). Yellow oil;

CH CN were added to a 100 mL stainless steel reactor. Then reactor

was closed tightly and pressurized with 8 atm of CO/O mixture

isolated through 40−200 mesh silica gel using pet ether:ethyl acetate

(

7:1) without ﬂushing. Then the reaction mixture was stirred with a

(70:30 v/v) mixture as eluent; isolated yield 69% (126.7 mg). H

mechanical stirrer at 100 °C for 12 h. After reaction completion, the

autoclave was cooled to room temperature and the remaining CO was

degassed carefully. The reaction mixture was diluted with ethyl acetate

NMR (400 MHz, CDCl ) δ 7.45 (d, 2H), 7.27 (t, 2H), 3.25 (d, 2H),

3.15−2.85 (m, 2H), 1.03 (s, 3H), 0.87 (s, 3H). C { H} NMR (101

MHz, CDCl ) δ 169.4, 140.7, 130.8 (C-F, J = 32 Hz), 130.5 (C-F,

C‑F

(

10 mL) and extracted with the aqueous solution, and the combined

J_C_‑_F= 32 Hz), 126.5, 125.1 (C-F, J = 3 Hz), 122.2, 43.0, 39.1,

C‑F

organic layer was dried over Na SO and concentrated under vacuum.

13.7, 12.4.

-Cyano-N,N-diethyl Benzamide (3k).

GC−MS analyzed the obtained crude product.

White solid; isolated

N,N-Diethylbenzamide (3a).

Colorless oil; isolated through

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

0−200 mesh silica gel using pet ether:ethyl acetate (70:30 v/v)

v/v) mixture as eluent; isolated yield 69% (104.5 mg). H NMR (400

mixture as eluent; isolated yield 87% (115.4 mg). H NMR (400

MHz, CDCl ): δ 7.31 (s, 5H), 3.48 (s, 2H), 3.20 (s, 2H), 1.17 (s,

MHz, CDCl ) δ 7.67 (d 2H), 7.43 (q, 2H), 3.51 (q, 2H), 3.16 (d,

2H), 1.22 (d, 3H), 1.08 (d, 3H). C { H} NMR (101 MHz, CDCl )

H), 1.06 (s, 3H). C { H} NMR (101 MHz, CDCl ) δ 171.2, 137.2,

δ 169.1, 141.5, 132.3, 127.0, 112.9, 43.2, 39.40, 14.1, 12.8.

28.9, 128.2, 126.1, 43.2, 39.2, 14.1, 12.8.

N,N-Diethylpicolinamide (3l). Yellow oil; isolated through 40−

N,N-Diethyl-4-methylbenzamide (3b).

Colorless oil; isolated

200 mesh silica gel using pet ether:ethyl acetate (60:40 v/v) mixture

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

as eluent; isolated yield 66% (88 mg). H NMR (400 MHz, CDCl ) δ

v/v) mixture as eluent; isolated yield 86% (123.1 mg). H NMR (400

8.53−8.48 (m, 1H), 7.70 (td, 1H), 7.49 (dd, 1H), 7.24 (dd, 1H), 3.50

MHz, CDCl ) δ 6.95 (dd, 2H), 6.91−6.71 (m, 2H), 3.18 (s, 2H),

(q, 2H), 3.30 (q, 2H), 1.20 (t, 3H), 1.08 (t, 3H). C { H} NMR

.96 (s, 2H), 2.03 (dd, 3H), 1.20−0.85 (s, 6H). C { H} NMR (101

(101 MHz, CDCl ) δ 168.5, 155.1, 148.2, 136.7, 123.9, 122.8, 43.09,

MHz, CDCl ) δ 170.7, 138.5, 134.1, 128.5, 126.0, 43.0, 40.9, 20.3,

40.0, 14.1, 12.7.

3.2.

N,N-Diethyl-2-methylbenzamide (3c).

N,N-Diethylthiophene-2-carboxamide (3m). Colorless oil;

Colorless oil; isolated

isolated through 40−200 mesh silica gel using pet ether:ethyl acetate

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

(60:40 v/v) mixture as eluent; isolated yield 67% (91.5 mg). H NMR

v/v) mixture as eluent; isolated yield 78% (111.7 mg). H NMR (400

(400 MHz, CDCl ) δ 7.39 (dd, 1H), 7.30 (dd, 1H), 7.04−6.98 (m,

MHz, CDCl ) δ 7.32−6.73 (m, 4H), 3.47 (d, 2H), 3.01 (dd, 2H),

1H), 3.52 (q, 4H), 1.23 (t, 6H). C { H} NMR (101 MHz, CDCl )

.18 (s, 3H), 1.16 (t, 3H), 0.92 (t, 3H). C { H} NMR (101 MHz,

δ 163.8, 138.2, 128.1, 127.9, 126.6, 29.6, 13.6.

CDCl ) δ 170.7, 137.0, 133.6, 130.1, 128.3, 125.6, 125.2, 42.5, 38.6,

N,N-Dipropylbenzamide (3n).

Colorless oil; isolated through

8.65, 13.8, 12.7.

N,N-Diethyl-4-methoxybenzamide (3d). Colorless oil; isolated

40−200 mesh silica gel using pet ether:ethyl acetate (70:30 v/v)

mixture as eluent; isolated yield 77% (118.3 mg). H NMR (400

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

MHz, CDCl ) δ 7.28 (s, 5H), 3.37−3.07 (s, 4H), 1.60−1.43 (s, 4H),

v/v) mixture as eluent; isolated yield 82% (127.3 mg). H NMR (400

0.89−0.64 (s, 6H). C { H} NMR (101 MHz, CDCl ) δ 171.5,

MHz, CDCl ) δ 7.24 (d, 2H), 6.80 (d, 2H), 3.71 (s, 3H), 3.31 (s,

137.2, 128.7, 128.1, 126.2, 50.5, 46.1, 21.9, 21.1, 11.2, 11.0.

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.1c00345.

Article

N,N-Dibutylbenzamide (3o).

Colorless oil; isolated through

δ 8.61 (d, 2H), 7.84−7.60 (m, 1H), 7.41−7.26 (m, 1H), 3.30 (dd,

0−200 mesh silica gel using pet ether:ethyl acetate (70:30 v/v)

mixture as eluent; isolated yield 74% (129.3 mg). H NMR (400

4H), 1.27−1.07 (m, 6H). C {H} NMR (101 MHz, CDCl ) δ 168.5,

150.2, 147.1, 134.2, 132.9, 123.3, 43.4, 39.5, 14.2, 12.8.

MHz, CDCl ) δ 7.38−7.23 (m, 5H), 3.47 (s, 2H), 3.16 (s, 2H),

4-Cyano-N,N-diethyl-3-methoxybenzamide (3z). Yellow oil;

isolated through 40−200 mesh silica gel using pet ether:ethyl acetate

.69−1.31 (m, 6H), 1.12 (s, 2H), 0.86 (d, 6H). C { H} NMR (101

MHz, CDCl ) δ 171.6, 137.3, 128.9, 128.2, 126.4, 48.7, 44.4, 30.7,

(70:30 v/v) mixture as eluent; isolated yield 52% (90.4 mg). H NMR

9.6, 20.26, 19.6, 13.8, 13.5.

N,N-Dihexylbenzamide (3p).

(400 MHz, CDCl ) δ 7.58 (dd, 1H), 7.02−6.93 (m, 2H), 3.95 (s,

Colorless oil. isolated through

3H), 3.55 (d, 2H), 3.22 (d, 2H), 1.27 (d, 6H). C {H} NMR (101

0−200 mesh silica gel using pet ether:ethyl acetate (70:30 v/v)

MHz, CDCl ) δ 169.1, 161.3, 143.1, 133.8, 118.2, 115.7, 109.5, 102.5,

−1

mixture as eluent; isolated yield 72% (156.2 mg). H NMR (400

56.2, 43.2, 39.4, 14.1, 12.7. IR (ATR)ν (cm ): 2935, 2233, 1636,

MHz, CDCl ) δ 7.32 (m, 5H), 3.49−3.24 (m, 2H), 3.20−3.08 (m,

1602, 1436−1465, 1261, 1032, 824. HRMS (ESI) m/z calcd for

H), 1.52−1.09 (m, 16H), 0.90−0.79 (m, 6H). C { H} NMR (101

[M + H] , 233.1290, found 233.1272.

MHz, CDCl ) δ 171.5, 128.9, 128.3, 126.3, 49.0, 47.4−47.2, 44.6,

2.1−41.9, 31.1, 28.5, 26.5, 26.2, 22.6, 13.9.

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

■

N,N-Dioctylbenzamide (3q).

Colorless oil; isolated through

0−200 mesh silica gel using pet ether:ethyl acetate (70:30 v/v)

mixture as eluent; isolated yield 75% (194.2 mg). H NMR (400

MHz, CDCl ) δ 7.32 (s, 5H), 3.44 (s, 2H), 3.13 (s, 2H), 1.61 (s, 2H),

.44 (s, 2H), 1.37−1.01 (m, 20H), 0.84 (s, 6H). C { H} NMR (101

Recycle study, control experiments, copies of H and C

spectra of products, IR, HRMS spectra of 3x and 3z

compounds (PDF )

MHz, CDCl ) δ 171.4, 137.3, 128.8, 128.1, 126.3, 48.9, 44.6, 31.6,

9.0, 27.4, 26.7, 22.5, 13.9.

N,N-Dimethylbenzamide (3r).

0−200 mesh silica gel using pet ether:ethyl acetate (70:30 v/v)

Colorless oil; isolated through

AUTHOR INFORMATION

Corresponding Author

mixture as eluent; isolated yield 71% (79.3 mg). H NMR (400 MHz,

CDCl ) δ 7.33 (s, 5H), 3.04 (s, 3H), 2.90 (s, 3H). C { H} NMR

■

(

101 MHz, CDCl ) δ 171.5, 136.2, 129.4, 128.2, 126.9, 39.4, 35.2.

16d

Bhalchandra M. Bhanage − Department of Chemistry,

Institute of Chemical Technology, Mumbai 400019, India;

orcid.org/0000-0001-9538-3339 ; Phone: +91 22

33612603; Email: bm.bhanage@ictmumbai.edu.in;

Fax: +91 22 33611020

N-Benzyl-N-methylbenzamide (3s).

Colorless oil; isolated

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

v/v) mixture as eluent; isolated yield 63% (106 mg). H NMR (400

MHz, CDCl ) δ 7.53−7.10 (m, 10H), 4.61 (d, 2H), 2.92 (d, 3H).

{

H} NMR (101 MHz, CDCl ) δ 169.0, 132.84, 129.9, 129.6, 128.8,

28.3, 127.5, 126.8, 55.1, 50.8, 37.0, 33.1.

N-Ethyl-N-phenyl Benzamide (3t).

Author

Colorless oil; isolated

Yuvraj A. Kolekar − Department of Chemistry, Institute of

Chemical Technology, Mumbai 400019, India

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

v/v) mixture as eluent; isolated yield 67% (113 mg). H NMR (400

MHz, CDCl ) δ 7.25 (dd, 2H), 7.22−7.15 (m, 3H), 7.11 (t, 3H),

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00345

.99 (d, 2H), 3.95 (q, 2H), 1.19 (t, 3H). C { H} NMR (101 MHz,

CDCl ) δ 170.1, 143.1, 136.2, 129.4, 129.0, 128.5, 127.8, 127.6, 126.5,

5.3, 12.9.

Phenyl (Piperidin-1-yl)methanone (3u). Colorless oil; isolated

Notes

The authors declare no competing ﬁnancial interest.

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

v/v) mixture as eluent; isolated yield 76% (107.5 mg) and 79% (111.5

ACKNOWLEDGMENTS

mg). H NMR (400 MHz, CDCl ) δ 7.26 (m, 5H), 3.58 (s, 2H), 3.21

(

■

s, 2H), 1.54 (s, 4H), 1.38 (s, 2H). C { H} NMR (101 MHz,

Y.A.K. gratefully acknowledges the University Grants Com-

mission (UGC), New Delhi, India, for the Senior Research

Fellowship (SRF) award.

CDCl ) δ 169.9, 136.3, 129.1, 128.1, 126.5, 48.4, 42.8, 27.8, 25.9,

4.2, 23.9.

Morpholino(phenyl)methanone (3v).

Colorless oil; isolated

through 40−200 mesh silica gel using pet ether:ethyl acetate (70:30

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■

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