Manganese Catalyzed Direct Amidation of Esters with Amines

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Zhengqiang Fu, Xinghua Wang, Sheng Tao, Qingqing Bu, Donghui Wei,* and Ning Liu*

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ABSTRACT: The transition metal catalyzed amide bond forming

reaction of esters with amines has been developed as an advanced

approach for overcoming the shortcomings of traditional methods.

The broad scope of substrates in transition metal catalyzed

amidations remains a challenge. Here, a manganese(I)-catalyzed

method for the direct synthesis of amides from a various number of

esters and amines is reported with unprecedented substrate scope

using a low catalyst loading. A wide range of aromatic, aliphatic, and

heterocyclic esters, even in fatty acid esters, reacted with a diverse

range of primary aryl amines, primary alkyl amines, and secondary alkyl amines to form amides. It is noteworthy that this approach

provides the ﬁrst example of the transition metal catalyzed amide bond forming reaction from fatty acid esters and amines. The

acid−base mechanism for the manganese(I)-catalyzed direct amidation of esters with amines was elucidated by DFT calculations.

a nole contribution in the acid−base mechanism^16a(Table 1,

INTRODUCTION

■

entry 1).

The amide bond is the most fundamental structural motif

In recent years, the transition metal catalyzed direct amide

found in natural products, pharmaceuticals, and biochemistry.¹

bond formation from esters and amines has received increasing

Approximately one-quarter of all marketed drugs and two-

attentions for its high reactivity and broad substrate scopes. A

thirds of all drug candidates contain at least one amide bond in

noble contribution to the transition metal catalysis ﬁeld for the

their chemical structure.²Conventional methods for the

direct synthesis of amide from esters and amines was recently

synthesis of amides involve reaction of carboxylic acids with

reported by Garg and co-workers¹⁷in 2016. They showed that

amines under harsh reaction conditions and/or in the presence

15 mol % of Ni(cod)₂and 30 mol % SIPr in toluene at 60 °C

of stoichiometric amounts of coupling reagents.³As a

in the presence of stoichiometric Al(OtBu)₃was suﬃcient to

consequence of the ubiquity of amide bonds, a sustainable

catalyze the amide bond formation reaction of methyl 1-

and atom-economic dehydrogenative coupling method for the

naphthoate esters with N-alkyl aniline derivatives. However,

synthesis of amides from the coupling of amines with alcohols

the substrate scopes for the direct amidation remains poor,

has been developed,⁴utilizing various transition metal

which limited exploration for more available substrates (Table

complexes as catalysts such as Mn,⁵Ru,⁶Rh,⁷Os,⁸Fe,⁹and

1, entry 5). Another contribution to this ﬁeld was reported by

Ag/Al₂O₃,¹⁰as well as a photocatalysis.¹¹

Newman and co-workers¹⁸in 2017. They employed a

Esters are one of the most fundamental organic molecules,

palladium complex as catalyst to be able to eﬀectively catalyze

which play a leading role in biologically active molecules,

the amidation reactions of phenyl esters and aryl amines to

chemical synthesis, and natural products. The direct synthesis

form amides. Despite the development is acquired in the

of amide from esters and amines is potentially the most useful

aforementioned method, the scope of esters and amines are

class of amide bond forming reactions in the synthetic

largely limited to aromatic esters and primary aryl amines

chemistry and pharmaceutical industries.¹²In the last ten

(Table 1, entry 6). In the next year, Newman et al.¹⁹reported

years, for the direct amidation of esters with amines, both

an extraordinary work that converted methyl esters and various

organocatalyzed¹³and metal-catalyzed¹⁴approaches have been

amines to amides using a Ni(cod)₂/IPr catalytic system with a

reported. Although extensively studied, the direct amidation of

broad range of substrates. However, a few substrates, including

esters with amines still shows some signiﬁcant challenges in the

second aryl amines, heteroaryl esters and fatty acid esters, are

area, including broadening the substrate scopes, the use of

abundant and commercially available metal catalysts, reducing

the use of additives, and decreasing the catalyst loading.¹⁵In

Received: October 19, 2020

Published: January 7, 2021

the past decade, several catalyst systems based on the acid−

base mechanism have been developed,¹⁶which have the

advantage of proceeding the reaction under mild reaction

conditions (Table 1, entries 1−4). In 2005, Porco and co-

workers reported a Zr(OtBu)₄/HOAt catalytic system, making

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Table 1. Strategies for Amide Bond Formation Using Esters and Aimines

a

Y (green) stands for moderate to excellent yields; N/R (red) stands for no reaction with experimental evidence; N/A (red) stands for

experimental data not available; and L (blue) stands for low yield of products. Alk_Istands for the primary alkyl amines; Alk_IIstands for the second

alkyl amines; Ar_Istands for the primary aryl amines; and Ar_IIstands for the second aryl amines.

not feasible for the catalytic system (Table 1, entry 7). Very

recently, Szostak and co-workers²⁰reported a promising metal-

free method under room temperature. Stoichiometric amounts

of LiHMDS (2 or 3 equiv) was used in this protocol, and some

substrates were not explored (Table 1, entries 8 and 9). Hu

and co-workers²¹reported an appealing strategy for reductive

amidation of methyl esters and nitroarenes using Ni(glyme)-

Cl₂/1,10-phenanthroline as catalysts and using a binary system

of Zn powder and chlorotrimethylsilane as a reductant.

for the direct amidations from esters and amines with a low

catalyst loading (1 mol %). It should be noted that this

protocol exhibits an unprecedented wide range of ester and

amine scopes and functional group tolerance (Table 1, entry

10).

RESULTS AND DISCUSSION

■

The pyridine-based pincer-type imidazolium salts L1-3 were

initially prepared according to our reported method.^24c−e

A

In spite of the encouraging progress in this area, there were

still some drawbacks existing in these methods: (1) high

catalyst loadings and additives were always required; (2)

limited substrate scopes. Hence, it is highly desirable to

develop a sustainable, powerful strategy for direct amidation to

access amide bonds from esters and amines. By the far, the

transition metal complexes associated with N-heterocyclic

carbenes (NHC)-based ligands are the most common catalytic

systems for the direct amidation of esters with amines. The

transition metal coordination based on hybrid ligands has

attracted wide interests in recent years.²²Hybrid ligands are

bidentate or polydentate ligands that contain at least two

donors with diﬀerent coordination abilities.²³The trans eﬀect

of hybrid ligands, such as NHC and nitrogen donors, leads to

unique properties and robust catalytic performance for the

resulting transition metal complexes. Based on our research in

the design and synthesis of catalysts,²⁴we now report a simple,

practical, and convenient synthetic procedure for Mn(I) pincer

complexes. The Mn(I) complexes show extremely high activity

simple and convenient method was developed for synthesis of

Mn(I) complexes. The synthesis was carried out via the

reaction of benzimidazolium salts L1-3 with MnBr(CO)₅

under nitrogen atmosphere, as shown in Scheme 1. Mn(I)

complexes 1a−c bearing an iodine anion were prepared via the

reactions of ligand L1 bearing an iodine anion with

MnBr(CO)₅in the presence of t-BuOK in tetrahydrofuran at

60 °C for 24 h (Scheme 1, top). The Mn(I) complex 1d

bearing a bromide anion was synthesized by employing

benzimidazolium salts bearing hexaﬂuorophosphate L2

(Scheme 1, middle). It is noteworthy that, in the case where

2,6-disubstituted pyridine-bridged benzimidazolium salts L3

was employed, the carbon atom at the C3 position on the

pyridine ring took part in coordination in comparison with

coordination of ligands L1 and L2 which coordinate with the

nitrogen atom bearing pyridine ring, aﬀording the Mn(I)

complex 1e (Scheme 1, bottom). The structures of the Mn

complexes 1b, 1d, and 1e were determined by X-ray

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Scheme 1. Manganese Pincer Complexes Used in This Work

crystallography, which conﬁrmed the atom connectivity of 1b,

1d, and 1e, as depicted in Scheme 1. All of the Mn complexes

were found to be air and moisture stable, even for 10 days

under an air atmosphere.

2). These results indicated that the coordination modes

between Mn and ligands were crucial for the overall reactivity

of the Mn complexes. The relatively strong electron-donor

ability of nitrogen donor (pyridine ring) compared with carbon

donor (benzene ring) is responsible for the results. The strong

coordination ability of nitrogen donor is beneﬁcial to stabilize

the Mn actvie species in catalytic cycles.

To further understand the inﬂuences of the N-substituted

alkyl in the benzimidazolium salts on the catalytic perform-

ance, alkyl chain length of N-substituents was explored. The

Mn complex 1b with a moderate length n-propyl chain (Table

2, entry 2) showed higher catalytic activity in comparison with

a Mn complex 1a with a shorter methyl chain (Table 2, entry

1) and Mn complex 1c with a longer n-butyl chain (Table 2,

entry 3). It is common knowledge that the butyl group has the

strongest electron-donor ability compared with the methyl and

propyl groups; however, the butyl group has a relatively high

steric hindrance. The strong electron-donor for the butyl group

is beneﬁcial to stabilize Mn active species in cycle; however,

the high steric hindrance prevents the removal of HI to

generate new active species. The propyl group possesses good

electron-donor ability and moderate size; therefore, the Mn

complex 1b bearing the propyl group showed a relatively high

performance.

In initial studies, the reaction of methyl benzoate (2a) with

4-methylaniline (3a) was used as a benchmark reaction to

optimize the reaction conditions (Table 2). To our delight, the

reaction proceeded eﬃciently under nitrogen atmosphere, with

the use of an extremely low catalyst loading (1 mol % of Mn

complex). Five diﬀerent coordination mode Mn complexes

1a−e were used as catalysts to investigate the inﬂuence of their

coordination modes and counteranions on catalytic perform-

ance (Table 2, entries 1−5). We were pleased to observe that

Mn complexes 1a−e resulted in a moderate to eﬃcient

catalytic system for the direct amidation of esters with amines

by using toluene as solvent and t-BuONa as base under 120 °C

(Table 2, entries 1−5).

The inﬂuence of coordination modes on the catalytic

performance of Mn complexes 1a-e was ﬁrst explored (Table 2,

entries 1−5). Mn complexes 1a−d coordinated with a nitrogen

atom bearing pyridine ring showed higher catalytic activity

compared with 1e which coordinated with a carbon atom

(Table 2, entries 1−4 vs 5). The most satisfactorily results

were obtained using Mn complex 1b as catalyst (Table 2, entry

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a

Table 2. Optimization of the Conditions for Direct Amidation

entry

cat. (mol %)

1a (1.0)

solvent

base (mol %)

T (°C)

time (h)

yield (%)

1

2

3

4

5

6

7

8

toluene

DMF

CPME

dioxane

MeCN

toluene

t-BuONa (20)

t-BuOK (20)

K₂CO₃(20)

120

100

120

18

12

28

18

46

85

57

49

27

65

16

20

45

51

30

6

62

53

88

76

56

83

52

63

87

70

trace

15

1b (1.0)

1c (1.0)

1d (1.0)

1e (1.0)

1b (1.0)

1b (1.5)

1b (0.8)

1b (0.5)

1b (1.0)

none

Cs₂CO₃(20)

K₃PO₄(20)

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

t-BuOLi (20)

t-BuONa (20)

t-BuONa (50)

t-BuONa (10)

t-BuONa (20)

none

t-BuONa (20)

MnBr(CO)₅(1.0)

MnCl₂(1.0)

MnBr₂(1.0)

1b (1.0)

b

28

a

Reaction conditions: methyl benzoate (1 mmol), amine (1.2 mmol), Cat. (1.0 mol %), solvent (1.5 mL), base (20 mol %), 120 °C for 18 h under

b

nitrogen atmosphere in a 25 mL Schlenk tube, and isolated yields. In air.

The inﬂuence of the counteranions bearing Mn complexes

1b and 1d on the catalytic performance was evaluated (Table

2, entries 2 and 4). As shown in Table 1, the Mn complex 1b

containing an iodine anion (Table 2, entry 2) was much more

eﬃcient than the Mn complex 1d containing a bromide anion

(Table 2, entry 4). The leaving ability of the halide anion is in

the following order: I⁻> Br⁻> Cl⁻. The strong leaving ability

of the iodine anion was beneﬁcial to generate Mn active

species, so that Mn complex 1b bearing idoine ainon exhibited

high catalytic activity.

Besides t-BuONa, others bases including t-BuOK, K₂CO₃,

Cs₂CO₃, and K₃PO₄were investigated under similar reaction

conditions (Table 2, entries 6−9), and t-BuONa was found to

be the most eﬀective for the transformation (Table 2, entry 2).

We supposed that the low solubility of t-BuONa led to the

poor result. Therefore, high solubility of t-BuOLi was

performed (Table 2, entry 10). The results indicated that

solubility of bases is not crucial for the performance. It is well-

known that t-BuOK has the strongest basicity among t-BuOLi,

t-BuONa, and t-BuOK, whereas t-BuOK has high steric

hindrance due to the bulkiness of potassium cation. The

stronger basicity for t-BuOK is beneﬁcial in removing the

hydrogen cation from the amino group; however, the high

steric hindrance prevents the hydrogen bond interaction

between t-BuOK and amines. t-BuONa possesses both strong

basicity and a moderate size, so that t-BuONa has a better

deprotonation ability on the amines. The inﬂuence of solvent

was also explored (Table 2, entries 11−14). When N,N-

dimethylformamide (DMF) and cyclopentylmethyl ether

(CPME) were employed, low yields for 4a were aﬀorded

(Table 2, entries 11 and 12). Other solvents, such as 1,4-

dioxane and MeCN, showed relatively low performance,

aﬀording a moderate yield of 4a (Table 2, entries 13 and

14). Furthermore, the inﬂuences of catalyst loading (Table 2,

entries 2 and 15−17) and t-BuONa of loading (Table 2,

entries 2, 18, and 19) were explored. In view of the cost, a

catalyst 1b loading of 1.0 mol % combined with a t-BuONa

loading of 20 mol % was appropriate (Table 2, entry 2). The

inﬂuences of reaction temperature (Table 2, entries 2 and 22)

and reaction time (Table 2, entries 2, 20, and 21) were also

evaluated, and it was shown that the desired product of 4a was

obtained in improved yield at the temperature of 120 °C,

together with a reaction time of 18 h which led to better results

(Table 2, entries 2).

Based on the above results, the combined use of Mn catalyst

1b and t-BuONa led to the best performance. However, it is

diﬃcult to trigger the reaction by employing the Mn complex

1b or t-BuONa on its own (Table 2, entries 23 and 24). In

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a

Table 3. Eﬀect of Boiling Point of Alcohol by-Product for Direct Amidation

entry

R

additive

yield (%)

bp of ROH (°C)

1

2

3

4

5

6

methyl

ethyl

n-pentyl

n-hexyl

methyl

0

85

82

64

41

21

0

65

78

136

157

65

5 equiv MeOH

10 equiv MeOH

65

a

Reaction conditions: methyl benzoate (1 mmol), amine (1.2 mmol), Cat. 1b (1.0 mol %), solvent (1.5 mL), base (20 mol %), 120 °C for 18 h

under nitrogen atmosphere in a 25 mL Schlenk tube, and isolated yields.

a

Table 4. Scope of Amines for the Synthesis of Amides

a

Reaction conditions: methyl benzoate (1.0 mmol), amine (1.2 mmol), cat. 1b (1.0 mol %), toluene (1.5 mL), t-BuONa (20 mol %), 120 °C for 18

b

h under nitrogen atmosphere in a 25 mL Schlenk tube, and isolated yields. 90 °C instead of 120 °C.

addition, several common Mn catalysts, such as MnBr(CO)₅,

MnBr₂, and MnCl₂, were tested in this reaction, and it was

indicated that they were hardly any activity (Table 2, entries

25−27). The results indicated that the pyridine-bridged

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a

Table 5. Scope of Amines and Esters

a

Reaction conditions: ester (1.0 mmol), amine (1.2 mmol), cat. 1b (1.0 mol %), toluene (1.5 mL), t-BuONa (20 mol %), 120 °C for 18 h under

b

c

d

e

f

g

nitrogen atmosphere in a 25 mL Schlenk tube, and isolated yields. 90 °C. Ethyl ester used instead of methyl ester. 100 °C. 80 °C. 50 °C. 60

°C. 5% ee (ester with 99% ee employed). 16% ee (ester with 97% ee employed). 1% ee (ester with 99% ee employed). 41% ee was obtained

with 30 mol % 4-CF₃−C₆H₄−OH as additive.

h

i

j

k

carbene ligands bearing Mn complexes played an important

role in the catalytic activity. Control experiments for the

atmosphere suggested that inert atmosphere protection was

necessary for a high conversion (Table 2, entries 2 vs 28). It is

likely that the oxygen in air signiﬁcantly inhibits the formation

of the active species.

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Next, we used the same substrate as that used in a previously

reported catalytic system under the optimized catalytic

conditions to compare their catalytic performance, respec-

tively, in Table S3 (see the Supporting Information for details).

The Mn-catalytic system showed a competitive catalytic

activity compared with other catalytic systems such as

Pd(IPr)(allyl)Cl, Ni(cod)₂/IPr, Zr(OtBu)₄/HOAt, and TBD

at high reaction temperature (Table S3, entries 3 vs 4, 5 vs 6, ;

7 vs 8, and 9 vs 10). However, the Mn-catalytic system is not

obviously superior among catalytic systems such as Ni(cod)₂/

SIPr and La(OTf)₃at a low reaction temperature (Table S3,

entries 1 vs 2 and 13 vs 14). It is noteworthy that the catalyst

loading in the Mn-catalytic system (1 mol %) is much lower

than that found in other catalytic systems (3−15 mol %).

The reactions of methyl benzoate with 4-methylaniline will

proceed well with the removal of methanol due to its

endergonic process. Although no process for methanol removal

was used in our experimental procedure, a better product yield

was achieved when methanol was achieved as a side product.

Therefore, the reason for these results was investigated in

Table 3 by employing esters with diﬀerent ester chain lengths.

As shown in Table 3, methyl and ethyl esters proceeded well

compared with those esters with longer ester chains such as n-

pentyl and n-hexyl esters. This is probably because the boiling

points of the methanol (65 °C) and ethanol (78 °C) generated

from methyl and ethyl esters are lower than the reaction

temperature (120 °C). Therefore, the methanol and ethanol

undergo vaporization to gather in the headspace of the reactor,

achieving the eﬀect of removing methanol and ethanol from

the reaction system (Table 3, entries 1 and 2). However, the

boiling points of pentanol (136 °C) and hexanol (157 °C) are

higher than the reaction temperature (120 °C). Thus, pentanol

and hexanol are diﬃcult to vaporize (Table 3, entries 3 and 4).

While the reactor is closed, the vaporized methanol only

gathered in the space above of the reactor, so the headspace of

the reactor plays a crucial role in the reaction eﬃciency. To

explore the eﬀect of the reaction headspace, an extra 5 or 10

equiv of methanol was added to the reactor, upon which the

yield for the products was found to be signiﬁcantly diminished

(Table 3, entry 5) or inhibited (Table 3, entry 6). In addition,

the eﬀect of the diﬀerent headspace volumes was evaluated,

and it was found that the product yield decreased from 85% to

66% when changing volumes from a 25 mL reactor to a 10 mL

reactor (see Figure S1 in the Supporting Information for

details). These results indicated that the large headspace at the

top of the reactor plays a role in removing the methanol

byproduct from the reaction system.

4w) and diphenylamine (Table 4, 4x) were found to show

moderate reactivity and were converted into the desired

products in moderate yields. The reactivity of 4-vinylaniline, 4-

ethynylaniline, and D-valine were also investigated in our

developed Mn-catalyzed system. However, no yields were

obtained (please see details in Scheme S2 in the Supporting

Information).

To investigate the scope of the reaction, a wide range of

ester and amines were evaluated (Table 5). Various esters

including aryl (Table 5, 5a−f), furan (Table 5, 5h−i and 5s−

u), N-heterocyclic (Table 5, 5j−q), naphthyl (Table 5, 5r),

thiophene (Table 5, 5v), oxazole (Table 5, 5w), thiazole

(Table 5, 5x), benzimidazole (Table 5, 5y), and alkyl

substituted groups (Table 5, 6a−d) smoothly reacted with

primary aryl amines (Table 5, 5a, 5b, 5d, 5g, 5h, 5j−n, 5t, 5v−

y, and 6a−d) and secondary alkyls (Table 5, 5e, 5f, 5i, 5o−s,

and 5u), resulting in moderate to excellent yields. We note that

5e is an important pharmaceutical used as a tubulin inhibitor

against cancer, which aﬀorded an excellent yield of 95%. It is

noteworthy that sterically hindered N-ortho-substituted ani-

lines (Table 5, 5k, 5m, and 5n) are readily tolerated, which led

to the production of valuable amides in moderate yields in the

Mn-catalyzed system. Heteroaromatic ring-substituted esters

were also investigated in Mn-catalyzed system. To our delight,

the amidation reaction using ethyl ester with thiophene,

thiazole and oxazole substituents took place to deliver the

desired amides 5v−x in excellent yields, respectively. The Mn-

catalyzed amidation reaction was not limited aromatic ester.

Indeed, the aliphatic esters including benzyl (Table 5, 6a),

morpholine (Table 5, 6b), cyclohexene (Table 5, 6c) and tert-

butyl group (Table 5, 6d) were also available substrates in Mn-

catalyzed system. The unsaturated esters such as methyl

cinnamate and methyl propiolate were tested in the Mn-

catalyzed catalyzed system, the useful functional groups such as

double bonds and triple bonds were converted to desired

product with high isolated yields (Table 5, 6e−h). In addition,

the enantiomerically pure esters at the α position such as

alpha-amino acid esters and mandelates were evaluated in our

developed Mn-catalyzed system, and high product yields were

obtained. The racemization of products was observed under

the optimized conditions (Table 5, 6i−k), we inferred that a

basic condition lead to α-amino acid derivatives racemization.

Ohshima and Mashima^16creported that the addition of acidic

alcohols such as triﬂuoromethylphenol eﬀectively inhibited the

racemization of the product. As expected, the ee% of product

6k was up to 41% by the addition of triﬂuoromethylphenol in

our developed catalytic system (Table 5, 6k).

Given high catalytic eﬃcacy of the Mn-catalyzed amidation,

we become interested in describing its mode of reaction. A

competition experiment was conducted using aniline as a

nucleophile by designing a substrate based on methyl 4-(2-

methoxy-2-oxoethyl)benzoate (Table 6). The results indicated

that benzylic esters were much more reactive than aryl esters,

providing single amidated aliphatic amide A and double

amidated amide B in 66% and 28% yields, respectively. By

simply optimization of reaction temperature and the molar

ratio of substrates (Table 6, entries 1−4), A was obtained as

the dominant product with a yield of 76% (Table 6, entry 4).

As shown in Scheme 2, the reactivity bewteen aryl esters and

alkyl esters was also evaluated. Methyl benzoate exhibited

higher reactivity than that of both methyl tetrahydro-2H-

pyran-4-carboxylate and methyl cyclohex-3-ene-1-carboxylate

(Scheme 2, eq 1 and 2). Based on the results above, the

To evaluate the scope of the amines, a wide range of amines

were investigated in the direct amidation of esters (Table 4).

The results suggested that a remarkably broad range of amines

are suitable for this Mn-catalyzed system. Both primary aryl

amines (Table 4, 4a−l) and primary alkyl amines (Table 4,

4m−t) were smoothly accommodated in this transformation.

Of particular note, primary alkyl amines such as benzylamine

(Table 4, 4m), 2-phenylethylamine (Table 4, 4n), cyclohexan-

amine (Table 4, 4p), and amylamine (Table 4, 4q) showed

higher reactivity than the primary aryl amines. The reactions of

primary alkyl amines still proceed well even under 90 °C,

giving excellent products yields. In addition, the secondary

alkyl amines containing N-heterocycles (Table 4, 4u and 4v)

and secondary alkyl/aryl or diaryl amines (Table 4, 4w and 4x)

were also evaluated in the Mn-catalyzed system. However,

N,N-disubstituted anilines such as N-methylaniline (Table 4,

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alcohol, which provide two possible reaction routes: the direct

amidation of aliphatic amine with methyl benzoate; the

transesteriﬁcation reaction of aliphatic alcohol with methyl

benzoate. In our developed Mn-catalyzed system, aliphatic

amine of aminoethanol reacted with highly site-selectivity with

methyl benzoate to give a hydroxyl amide D with highly site-

selectivity (Scheme 3, eq 4).

Table 6. Selective Amidation of Diﬀerent Esters with

Aniline

a

The reaction of benzoic acid or benzamide with aniline was

investigated, respectively, in our developed catalytic system.

However, the reaction of benzoic acid with aniline did not

produce desired product (see details in Scheme S1 in the

Supporting Information). The benzamide could react with

aniline, giving 10% yield (see details in Scheme S1 in the

Supporting Information).

T

isolated yield of A

isolated yield of B

entry (°C)

aniline

(%)

1

2

3

4

120

90

60

2 equiv

1.2 equiv

66

70

52

76

28

13

0

trace

Newman and co-workers^19ahave described that the utility of

fatty acid esters as electrophiles for synthesis of plant-oil-based

amides remains a challenge. The application for synthesis of

amides from biomass is a particularly attractive alternative

because it facilitates a shift from the use of fossil resources to

renewable resources. Encouraged by the aforementioned

promising results, several fatty acid esters and their derivatives

were explored in our established protocol (Table 7). We were

delighted to ﬁnd that methyl oleate smoothly amidated with 2-

phenylethan-1-amine to give 7a in a yield of 77%, even at a

relatively low reaction temperature (90 °C). Under similar

conditions, the desired product of 7a was obtained in a yield of

75% when ethyl oleate was employed as the electrophiles.

Epoxidized methyl oleate was successfully amidated with 2-

phenylethan-1-amine and aniline, delivering the products 7b

and 7c with good yields of 75% and 71%, respectively. Other

plant-oil-based fatty acid esters, such as methyl eruclate, methyl

linoleate, and especially methyl undecylenate, were found to be

compatible with current standard conditions, furnishing the

desired plant oil-based products 7d−f in yields of 81%, 67%

and 86%, respectively. To the best of our knowledge, no

transition metal catalyzed amidation of fatty acid esters with

amines are known, only Ni- or Mn-catalyzed reductive

amidation of nitroarenes have been sucessfullly used in the

synthesis of amides from fatty acid esters.^21,25

90

a

Reaction conditions: methyl 4-(2-methoxy-2-oxoethyl)benzoate (1.0

mmol), aniline (indicated as Table 6), Cat. (1.0 mol %), solvent (1.5

mL), base (20 mol %), 120 °C for 18 h under nitrogen atmosphere in

a 25 mL Schlenk tube, and isolated yields.

reactivity of esters is in the following order: benzylic esters >

aryl esters > alkyl esters (Table 6 and Scheme 2).

Additionally, an intermolecular competitive reactions of

aniline and benzylamine with methyl benzoate or aniline and

cyclohexanamine with methyl benzoate were explored,

respectively, in Scheme 3. The methyl benzoate preferentially

reacted with benzylamine rather than aniline to generate the

desired product 4m (Scheme 3, eq 1). This result suggested

that benzylamine showed higher reactivity than aniline. In

addition, the reactivity diﬀerence between aniline and

cyclohexylamine was investigated (Scheme 3, eq 2). The

result suggested that cyclohexylamine showed higher reactivity

than aniline. The reactivity diﬀerence between the primary

alkyl amines and the secondary alkyl amines was investigated

by using methyl benzoate as a reaction partner. The catalytic

system showed high selectivity for diﬀerent amino groups, and

direct amidation site-selectively occurred at the primary alkyl

amines to give product C in 85% yield (Scheme 3, eq 3).

Aminoethanols bearing both an aliphatic amine and aliphatic

Scheme 2. Selective Amidation of Diﬀerent Esters

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Scheme 3. Selective Amidation of Diﬀerent Amines

a

Table 7. Synthesis of Amides from a Fatty Acid Ester

a

Reaction conditions: fatty acid ester (1.0 mmol), amine (1.2 mmol), cat. 1b (1.0 mol %), toluene (1.5 mL), t-BuONa (20 mol %), 90 °C for 18 h

b

under nitrogen atmosphere in a 25 mL Schlenk tube, and isolated yields. Ethyl ester used instead of methyl ester.

To further demonstrate the compatibility of this protocol,

we next proceeded to explore the scope of diﬀerent ester

precursors, since some common esters are not compatible with

the reported transition metal-catalyzed systems.¹²As shown in

Table 8, various esters, such as ethyl (Table 8, 8a), benzyl

(Table 8, 8d), aryl (Table 8, 8e), and sterically hindered iso-

propyl (Table 8, 8b) and tert-butyl ester (Table 8, 8c), were

found to be suitable electrophiles partners with moderate to

high yields for products.

To demonstrate the synthetic application of this Mn-

catalyzed amide bond forming approach, the method was

applied to the synthesis of substituted amide-containing drugs,

such as tigan E and itopride F (Scheme 4),²⁶from benzyl

amine and aryl methyl ester. We found that the optimized

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a

Table 8. Scope of Other Esters

a

Reaction conditions: ester (1.0 mmol), aniline (1.2 mmol), cat. 1b (1.0 mol %), toluene (1.5 mL), t-BuONa (20 mol %), 120 °C for 18 h under

b

nitrogen atmosphere in a 25 mL Schlenk tube, and isolated yields. 140 °C instead of 120 °C.

Scheme 4. Synthetic Application for the Synthesis of Tigan and Itopride

Scheme 5. Gram-Scale Synthesis

reaction conditions are also well-compatible with direct amide

bond forming reaction for the synthesis of the two amide-

containing drugs E and F, aﬀording a high yield of 81% and

78%, respectively.

In addition, a gram-scale experiment was carried out under

the optimized conditions. The reaction of methyl 3,4,5-

trimethoxybenzoate with indoline was easily scaled up to the

gram scale to give 5e with a yield of 85% under the optimized

reaction conditions (Scheme 5).

We performed kinetic experiment to determine the order of

reaction. Plots of k_inversus the concentrations of methyl

benzoate and the catalyst gave linear curves (slope = 2.558 ×

10⁻⁵M s⁻¹; 1.69 × 10⁻⁵M s⁻¹) indicating a ﬁrst order rate

dependence on methyl benzoate and the catalyst (Figures S15b

and S17b in the Supporting Information). Similar kinetic

studies by varying the concentration of amine, however,

showed no change in k_in(Figure S16b in the Supporting

Information) suggesting that the reaction is zero order on

amine.

DFT calculations were performed to explore the possible

mechanisms for the Mn-catalyzed reaction of amine and ester.

As shown in Figure 1, two kinds of mechanisms including a

oxidative addition-reductive elimination mechanism¹⁷(red

line) and acid−base mechanism^16a,20b(black line) were

considered and investigated at the B3LYP-D3/6-311+G(d,

p)/SDD/SMD_toluene//B3LYP/6-31G(d, p)/SDD/SMD_toluene

level. For the acid−base mechanism, there are three stages

that are involved in the reaction. First, the deprotonation of the

primary amine by the t-BuO⁻ion occurs smoothly via

transition state 2-ts with an energy barrier of 0.2 kcal/mol.

Second, the complex of Mn-coordinated with the deprotonated

amine (the transition state 4 was supported by IR experiments;

see Figure S13 in the Supporting Information for details)

nucleophilically attacks the carbonyl carbon of ester for the C−

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Figure 1. Energy proﬁles for the oxidative addition-reductive elimination mechanism (red line) and acid−base mechanism (black line) for the Mn-

catalyzed reaction (distances in Å).

N bond formation via transition state 5-ts, which is followed by

the dissociation of the amide product via transition state 7-ts.

Third, the CH₃O⁻ion is protonated by the in situ generated t-

BuOH via transition state 9-ts. The second stage has the

highest energy barrier of 30.2 kcal/mol and should be the rate-

determining step. For the oxidative addition-reductive

elimination mechanism, we have tried but failed to ﬁnd the

transition state via construction of the actual catalyst-mediated

reaction model, and the proposed oxidative intermediate 12

has an extremely high energy (104.6 kcal/mol) related to the

reactant. Therefore, the calculation results are better

rationalized by the acid−base mechanism.

DFT methods. The results indicated that the energy barrier for

MnBrCO₅(41.5 kcal/mol) was higher than that of Mn

complex 1b (30.2 kcal/mol; Figure 2). The energy barriers

diﬀerences between Mn complex 1b and MnBrCO₅explained

why Mn complex 1b worked better than MnBrCO₅. In

addition, the sodium countercation was also included in DFT

calculations. As shown in Figure 2, the energy barrier

diﬀerence between containing sodium ion and noncontaining

sodium ion is approximative (Figure 2, 30.2 vs 33.3 kcal/mol),

so it will not have an eﬀect for the whole DFT calculation

results in Figure 1. The inﬂuence of the position of anion in

Mn complexes was calculated by removing the iodine anion

from 4 and removing the bromide anion from 4″, respectively

(Figure 2). The results indicated that the position of the anion

in Mn complexes has no evident eﬀect in the energy barrier

To gain insights into the mechanism, we perfomed

theoretical calculations to clarify the reason for the diﬀerence

in catalytic activity of MnBr(CO)₅and Mn catalyst 1b by using

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Figure 2. Comparison of energy barriers.

Preparation of Single Crystals. The crystalline material was

prepared via a layer-to-layer diﬀusion method. The manganese

complex 1b was added into a dichloromethane solution; the

manganese complex 1d was added into a mixture solution of

acetonitrile/ethyl ether = 5:1; the manganese complex 1e was added

into the mixture solution of dichloromethane/hexane = 5:1. After 3−5

days, a crystal suitable for single-crystal X-ray diﬀraction was obtained.

Crystallographic data for the structures of the manganese complexes

1b, 1d, and 1e were deposited in the Cambridge Crystallographic

Database Centre, supplementary publication Nos. CCDC 1965826,

1965828, and 1961734 for manganese complexes 1b, 1d, and 1e,

respectively.

Analytical Methods. The NMR spectra were recorded using a

Bruker Avance III HD 400 spectrometer using TMS as the internal

standard (400 MHz for ¹H NMR and 100 MHz for ¹³C NMR). Mass

spectroscopy data were collected by using a Shimadzu LCMS-IT-

TOF mass spectrometer. The determination of enantiomeric excess

was performed by chiral phase HPLC analysis using an Water UPCC

instrument and DAICEL CHIRALCEL AD-H column. FT-IR spectra

were recorded on Tianjin Gangdong FTIR-650. Single crystal

structure determination was conducted using a Bruker D8 Venture

X-ray diﬀractometer equipped with a PHOTON II CPAD detector.

Preparation Procedure for Catalysts 1a−1d. The synthesis of

ligands has been reported previously in our works.^24c−eThe

manganese complexes were synthesized based on previous liter-

ature.²⁷A mixture of MnBr(CO)₅(0.5 mmol, 1.0 equiv), ligand (0.6

mmol, 1.2 equiv), and t-BuOK (0.5 mmol, 1.0 equiv) was stirred in a

25 mL of Schlenk tube, and the reaction tube was vacuumed and then

ﬁlled with nitrogen three times under the Schlenk system.

Subsequently, THF (2 mL) was added to the reaction tube, and

then the mixture was stirred in a heating mantle at 60 °C for 24 h.

After cooling to room temperature, THF was removed under reduced

pressure using a rotary evaporator. The reaction mixtures were then

further washed with acetonitrile (3 × 10 mL) to remove unreacted

ligand and MnBr(CO)₅, and the crude products were ﬁltered and

dried to give the desired product.

diﬀerence (Figure 2, 30.2 vs 32.8 kcal/mol and 41.5 vs 40.4

kcal/mol).

CONCLUSION

■

In conclusion, we report for ﬁrst time a manganese-catalyzed

amide bond forming reaction with a broad range of esters and

amines. The manganese-catalyzed approach exhibits ultra-

strong catalytic activity and unprecedented scope for substrates

in the ﬁeld of transition metal catalyzed direct amidation of

esters with amines. This catalytic system allows for the use of

broad scopes of aromatic, aliphatic, heterocyclic, and fatty acid

esters, and various primary aryl amines, primary alkyl amines,

as well as secondary alkyl amines, tolerating a diverse range of

functional groups and aﬀording a wide range of amides with

excellent yields. It is crucial to note that this method provides

the ﬁrst example for the synthesis of plant-oil-based amides

from fatty acid esters and amines. The competition experiment

for esters indicates that alkyl ester is much more reactive than

aryl ester. The competition experiment for amines shows that

the reactivity of benzylamine is higher than that of aniline and

that the primary alkyl amines show higher reactivity than the

secondary alkyl amines. DFT calculations suggest that the

manganese(I)-catalyzed direct amidation of esters with amines

occurs via an acid−base mechanism rather than an oxidative

addition-reductive elimination process. This approach provides

more eﬀective and sustainable alternatives for challenging

substrates to gain access to amide-containing drugs.

EXPERIMENTAL SECTION

■

General Information. Unless otherwise stated, all experimental

procedures were performed under an atmosphere of nitrogen using

Schlenk techniques. All solvents, esters, amines, and other starting

materials were purchased from commercial suppliers and used

without further puriﬁcation.

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Preparation Procedure for Catalyst 1e. A mixture of

MnBr(CO)₅(0.5 mmol, 1.0 equiv), ligand (0.6 mmol, 1.2 equiv),

and t-BuOK (0.5 mmol, 1.0 equiv) was stirred in a 25 mL Schlenk

tube, and the reaction tube was vacuumed and then ﬁlled with

nitrogen three times under the Schlenk system. Subsequently, THF

(2.0 mL) was added to the reaction tube, and then the mixture was

stirred in a heating mantle at 60 °C for 24 h. After cooling to room

temperature, THF was removed under reduced pressure using a

rotary evaporator, and the gray solid product of 1e was isolated by

ﬂash chromatography (petroleum ether (PE)/ethyl acetate (EA) =

5:1).

General Procedure for Amides. Methyl ester (1 mmol), amine

(1.2 mmol), Mn catalyst (1.0 mol %), and base (20 mol %) were

added to a 25 mL Schlenk tube that was equipped with a magnetic

stirrer. The reaction tube was vacuumed and then ﬁlled with nitrogen

three times under the Schlenk system. Subsequently, toluene (1.5

mL) was added to the reaction tube. The reactor was stirred in a

heating mantle at the speciﬁed temperature for 18 h. After cooling to

room temperature, the solvent was removed under reduced pressure,

and the products were isolated by ﬂash chromatography.

Gram-Scale Synthesis. 3,4,5-Trimethoxybenzoate (5 mmol, 1.15

g), indoline (6 mmol), Mn catalyst 1b (1.0 mol %, 25.2 mg), and t-

BuONa (20 mol %, 97 mg) were added to a 50 mL Schlenk tube that

was equipped with a magnetic stirrer. The reaction tube was

vacuumed and then ﬁlled with nitrogen three times under the

Schlenk system. Subsequently, toluene (4 mL) was added to the

reaction tube. The reactor was stirred in a heating mantle at 120 °C

for 18 h. After cooling to room temperature, the solvent was removed

under reduced pressure, and the products were isolated by ﬂash

chromatography to give product 5e in 85% yield (1.33 g).

NMR (400 MHz, CDCl₃): δ 7.92 (brs, 1H), 7.86−7.84 (m, 2H),

7.55−7.51 (m, 3H), 7.45 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H),

2.34 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 165.9, 135.5,

135.2, 134.3, 131.8, 129.7, 128.8, 127.1, 120.5, 21.0.

N-(4-Fluorophenyl)benzamide (4b).²⁸4b was prepared according

to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 10:1): a white solid (167.8 mg, 78%), mp = 184.6−185.1

°C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.31 (s, 1H), 7.97−7.95 (m,

2H), 7.83−7.78 (m, 2H), 7.62−7.52 (m, 3H), 7.20 (t, J = 8.8 Hz,

2H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 165.9, 158.8 (d, J =

239 Hz), 136.0, 135.3, 132.1, 128.9, 128.1, 122.6 (d, J = 7.8 Hz),

115.6 (d, J = 22 Hz).

N-(p-Methoxyphenyl)benzamide (4c).^19a4c was prepared accord-

ing to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 10:1): a white solid (183.9 mg, 81%), mp = 156.2−157.2

°C. ¹H NMR (400 MHz, CDCl₃): δ 7.85(d, J = 7.2 Hz, 2H),

7.79(brs, 1H), 7.55−7.52 (m, 3H), 7.47 (t, J = 7.6 Hz, 2H), 6.90 (d, J

= 9.2 Hz, 2H), 3.81 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

165.8, 156.9, 135.2, 131.9, 131.1, 128.9, 127.1, 122.3, 114.4, 55.7.

N-(4-Iodophenyl)benzamide (4d).²⁹4d was prepared according to

the general procedure. Puriﬁcation by column chromatography (PE/

EA = 10:1): a white solid (213.1 mg, 66%), mp = 216.4−217.8 °C. ¹H

NMR (400 MHz, DMSO-d₆): δ 10.33 (s, 1H), 7.94 (d, J = 7.2 Hz,

2H), 7.70−7.68 (m, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 7.6

Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H). ¹³C{¹H} NMR (100 MHz, DMSO-

d₆): δ 165.6, 139.0, 137.3, 134.7, 131.7, 128.4, 127.7, 122.4, 87.3.

N-Phenylbenzamide (4e).¹⁸4e was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

1

10:1): a white solid (153.7 mg, 78%), mp = 157.6−158.2 °C. H

NMR (400 MHz, CDCl₃): δ 7.91 (brs, 1H), 7.88−7.85 (m, 2H),

7.65−7.63 (m, 2H), 7.56−7.53 (m, 1H), 7.49−7.45 (m, 2H), 7.37 (t,

J = 7.6 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 165.9, 138.1, 135.2, 132.0, 129.3, 129.0, 127.1, 124.7,

120.3.

Manganese Complexes (1a). 1a was prepared according to the

1

general procedure. A yellow-orange solid (161.8 mg, 76%). H NMR

(400 MHz, DMSO-d₆): δ 9.07 (brs, 1H), 8.49 (d, J = 36.8 Hz, 2H),

8.25 (brs, 1H), 7.94 (brs, 1H), 7.57 (brs, 3H), 4.29 (s, 3H). Mn

complex 1a is paramagnetic, and ¹³C NMR spectra were not obtained.

HRMS (ESI-TOF) m/z: [M-I]⁺Calcd for C₁₆H₁₁MnN₃O₃348.0175;

Found 348.0179.

N-Benzoyl-2-methylaniline (4f).^19a4f was prepared according to

the general procedure. Puriﬁcation by column chromatography (PE/

EA = 10:1): a yellow solid (171.1 mg, 81%), mp = 144.1−144.6 °C.

¹H NMR (400 MHz, CDCl₃): δ 7.89−7.85 (m, 3H), 7.76 (brs, 1H),

7.56−7.52 (m, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.25−7.20 (m, 2H),

7.12−7.08 (m, 1H), 2.31 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃):

δ 165.8, 135.9, 135.1, 131.9, 130.7, 129.7, 128.9, 127.2, 126.9, 125.5,

123.5, 17.9.

Manganese Complexes (1b). 1b was prepared according to the

1

general procedure. A yellow-orange solid (163.8 mg, 73%). H NMR

(400 MHz, DMSO-d₆): δ 9.07 (brs, 1H), 8.49 (d, J = 34.8 Hz, 2H),

8.25 (brs, 1H), 8.01 (brs, 1H), 7.56 (brs, 3H), 4.70 (s, 2H), 2.07 (brs,

2H), 1.06 (s, 3H). Mn complex 1b is paramagnetic, and ¹³C NMR

spectra were not obtained. HRMS (ESI-TOF) m/z: [M-I]⁺Calcd for

C₁₈H₁₅MnN₃O₃376.0488; Found 376.0496.

N-(2-Cyanophenyl)benzamide (4g).³⁰4g was prepared according

to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 10:1): a white solid (139.5 mg, 63%), mp = 157.6−158.4

°C. ¹H NMR (400 MHz, CDCl₃): δ 8.61 (d, J = 8.4 Hz, 1H), 8.41 (s,

1H), 7.96−7.93 (m, 2H), 7.68−7.59 (m, 3H), 7.56−7.52 (m, 2H),

7.22 (d, J = 7.6 Hz, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 165.6,

140.8, 134.5, 133.8, 132.8, 132.3, 129.3, 127.3, 124.4, 121.2, 116.6,

102.2.

Manganese Complexes (1c). 1c was prepared according to the

1

general procedure. A yellow-orange solid (147.6 mg, 68%). H NMR

(400 MHz, DMSO-d₆): δ 9.07 (brs, 1H), 8.49 (d, J = 35.2 Hz, 2H),

8.24 (brs, 1H), 7.98 (brs, 1H), 7.57 (brs, 3H), 4.73 (s, 2H), 2.07 (brs,

2H), 1.50 (brs, 2H), 1.06 (s, 3H). Mn complex 1c is paramagnetic,

and ¹³C NMR spectra were not obtained. HRMS (ESI-TOF) m/z:

[M-I]⁺Calcd for C₁₉H₁₇MnN₃O₃390.0645; Found 390.0656.

Manganese Complexes (1d). 1d was prepared according to the

N-(3-Nitrophenyl)benzamide (4h).³¹4h was prepared according

to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 10:1): a white solid (181.5 mg, 75%), mp = 120.0−122.7

1

general procedure. A yellow-orange solid (164.2 mg, 81%). H NMR

1

°C. H NMR (400 MHz, CDCl₃): δ 8.50 (s, 1H), 8.11−8.00 (m,

(400 MHz, DMSO-d₆): δ 8.46−7.62 (m, 8H), 4.77 (brs, 2H), 2.08

(brs, 2H), 1.24−1.09 (m, 3H). Mn complex 1d is paramagnetic, and

¹³C NMR spectra were not obtained. HRMS (ESI-TOF) m/z: [M-

Br]⁺Calcd for C₁₈H₁₅MnN₃O₃376.0488; Found 376.0502. Similar

structure to compound 1d has been reported previously.^27b

3H), 7.91−7.88 (m, 2H), 7.62−7.58 (m, 1H), 7.55−7.50 (m, 3H),.

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 166.0, 148.8, 139.2, 134.2,

132.6, 130.1, 129.2, 127.2, 126.0, 119.3, 115.0.

N-(Pyridin-2-yl)benzamide (4i).^20b4i was prepared according to

the general procedure. Puriﬁcation by column chromatography (PE/

Manganese Complexes (1e). 1e was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

5:1): a gray solid (84.6 mg, 45%). ¹H NMR (400 MHz, DMSO-d₆): δ

8.81−8.79 (m, 2H), 8.27 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz,

1H), 7.84 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.58−7.53 (m, 2H), 6.64

(s, 1H) 4.59 (t, J = 7.6 Hz, 2H), 1.99−1.94 (m, 2H), 1.04 (t, J = 7.2

Hz, 3H). Mn complex 1e is paramagnetic, and ¹³C NMR spectra were

not obtained. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₂₂H₁₇MnN₅O₄470.0656; Found 470.0652.

1

EA = 5:1): a white solid (170.3 mg, 86%), mp = 78.2−78.6 °C. H

NMR (400 MHz, CDCl₃): δ 9.49 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H),

8.03 (d, J = 4.0 Hz, 1H), 7.92−7.90 (m, 2H), 7.70 (t, J = 8.4 Hz, 1H),

7.51 (t, J = 7.6 Hz, 1H), 7.45−7.40 (m, 2H) 6.98−6.95 (m, 1H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 166.3, 151.9, 147.7, 138.5,

134.5, 132.1, 128.7, 127.5, 119.8, 114.5.

N-(Pyridin-4-yl)benzamide (4j).¹⁸4j was prepared according to

the general procedure. Puriﬁcation by column chromatography (PE/

EA = 1:1): a white solid (154.5 mg, 78%), mp = 202.5−204.6 °C. ¹H

NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 1H), 8.48 (d, J = 5.6 Hz,

2H), 7.98−7.96 (m, 2H), 7.81−7.79 (m, 2H), 7.63 (t, J = 7.6 Hz,

N-(p-Tolyl)benzamide (4a).^20b4a was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

1

15:1): a white solid (179.4 mg, 85%), mp = 160.2−162.4 °C. H

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1H), 7.55 (t, J = 7.6 Hz, 2H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆):

δ 166.5, 150.3, 145.9, 134.3, 132.1, 128.5, 127.9, 114.0.

N-(Cyclopropylmethyl)benzamide (4s).³⁴4s was prepared accord-

ing to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 5:1): a white solid (145.3 mg, 83%), mp = 75.6−76.1 °C.

¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, J = 7.2 Hz, 2H), 7.46 (t, J =

7.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 6.49 (brs, 1H), 3.28 (t, J = 6.8

Hz, 2H), 1.08−1.00 (m, 1H), 0.54−0.50 (m, 2H), 0.24 (q, J = 4.8 Hz,

2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 167.6, 134.8, 131.4, 128.5,

127.0, 45.0, 10.8, 3.6.

N-1-Naphthalenyl-benzamide (4k).^19a4k was prepared according

to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 10:1): a white solid (183.9 mg, 74%), mp = 162.3−163.4

1

°C. H NMR (400 MHz, CDCl₃): δ 8.28 (brs, 1H), 8.00−7.97 (m,

3H), 7.92−7.87 (m, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.61−7.57 (m,

1H), 7.53−7.50 (m, 5H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

166.4, 134.9, 134.3, 132.5, 132.1, 129.0, 128.9, 127.6, 127.3, 126.5,

126.3, 126.2, 125.9, 121.5, 120.9.

N-((Tetrahydrofuran-2-yl)methyl)benzamide (4t).^19a4t was

prepared according to the general procedure. Puriﬁcation by column

N-([1,1′-Biphenyl]-2-yl)benzamide (4l).^19a4l was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 20:1): a white solid (152.9 mg, 56%),

mp = 90.2−91.4 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.40 (d, J = 8.4

Hz, 1H), 7.93 (s, 1H), 7.50−7.47 (m, 2H), 7.40−7.27 (m, 7H),

7.26−7.22 (m, 2H), 7.19−7.16 (m, 1H), 7.11−7.07 (m, 1H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 165.0, 138.1, 134.9, 134.8,

132.6, 131.7, 130.0, 129.4, 129.2, 128.7, 128.6, 128.2, 126.8, 124.5,

121.4.

1

chromatography (PE/EA = 5:1): a brown oil (155.9 mg, 76%). H

NMR (400 MHz, CDCl₃): δ 7.78 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.2

Hz, 1H), 7.44−7.40 (m, 2H), 6.57 (brs, 1H), 4.06 (qd, J = 7.2, 3.6

Hz, 1H), 3.91−3.86 (m, 1H), 3.81−3.74 (m, 2H), 3.33 (ddd, J =

1.24, 7.6, 5.2 Hz, 1H), 2.06−1.98 (m, 1H), 1.95−1.88 (m, 2H),

1.65−1.56 (m, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 167.7,

134.7, 131.5, 128.6, 127.1, 77.9, 68.3, 43.7, 28.8, 26.0.

Indolin-1-yl(phenyl)methanone (4u).^20b4u was prepared accord-

ing to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 10:1): a white solid (207.5 mg, 93%), mp = 125.0−127.1

N-Benzylbenzamide (4m).^19a4m was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

5:1): a white solid (185.8 mg, 88%), mp = 104.5−105.1 °C. ¹H NMR

(400 MHz, CDCl₃): δ 7.78−7.75 (m, 2H), 7.44 (t, J = 7.2 Hz, 1H),

7.35 (t, J = 7.6 Hz, 2H), 7.30−7.22 (m, 5H), 6.88 (brs, 1H), 4.56 (d, J

= 5.6 Hz, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 167.6, 138.4,

134.4, 131.5, 128.7, 128.5, 127.8, 127.5, 127.1, 44.0.

1

°C. H NMR (400 MHz, CDCl₃): δ 8.16 (brs, 1H), 7.56−7.54 (m,

2H), 7.47−7.42 (m, 3H), 7.26−7.20 (m, 2H), 7.02 (brs, 1H), 4.08 (s,

2H), 3.12 (t, J = 8.4 Hz, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

169.1, 142.7, 137.1, 132.5, 130.4, 128.7, 127.2, 125.0, 124.0, 117.4,

50.9, 28.2.

(3,4-Dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (4v).^19a4v

was prepared according to the general procedure. Puriﬁcation by

column chromatography (PE/EA = 5:1): a colorless oil (203.9 mg,

N-Phenethylbenzamide (4n).^19a4n was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

5:1): a white solid (213.9 mg, 95%), mp = 116.2−118.0 °C. ¹H NMR

(400 MHz, CDCl₃): δ 7.70 (d, J = 6.8 Hz, 2H), 7.45 (t, J = 7.2 Hz,

1H), 7.36 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 6.8 Hz, 2H), 7.24−7.20 (m,

3H), 6.50 (brs, 1H), 3.70−3.65 (m, 2H), 2.90 (t, J = 6.8 Hz, 2H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 167.6, 139.0, 134.7, 131.4,

128.8, 128.7, 128.5, 126.9, 126.6, 41.3, 35.7.

1

86%). H NMR (400 MHz, C₆D₆): δ 7.37−7.34 (m, 2H), 7.16 (s,

1H), 7.08−7.04 (m, 3H), 7.00−6.96 (m, 2H), 6.82 (d, J = 8.0 Hz,

1H), 4.80−4.30 (m, 2H), 3.76−3.12 (m, 2H), 2.35 (brs, 2H).

¹³C{¹H} NMR (100 MHz, C₆D₆): δ 170.1, 137.2, 134.6, 133.7, 129.7,

129.0, 128.5, 127.7, 127.4, 126.7, 126.6, 49.5, 45.2, 29.4.

N-Methyl-N-phenylbenzamide (4w).^20b4w was prepared accord-

ing to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 10:1): a white solid (97.1 mg, 46%), mp = 47.8−48.6 °C.

¹H NMR (400 MHz, CDCl₃): δ 7.37 (d, J = 6.8 Hz, 2H), 7.30−7.26

(m, 3H), 7.22−7.17 (m, 3H), 7.10 (d, J = 8.0 Hz, 2H), 3.57 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 170.6, 144.8, 135.9, 129.5,

129.1, 128.6, 127.7, 126.8, 126.4, 38.3.

N-(1-Phenylethyl)benzamide (4o).^19a4o was prepared according

to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 5:1): a white solid (193.6 mg, 86%), mp = 91.2−93.6 °C.

¹H NMR (400 MHz, CDCl₃): δ 7.76 (d, J = 8.4 Hz, 2H), 7.46 (t, J =

7.2 Hz, 1H), 7.40−7.32 (m, 6H), 7.28−7.24 (m, 1H), 6.53 (brs, 1H),

5.36−5.29 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 166.7, 143.3, 134.7, 131.5, 128.8, 128.6, 127.5,

127.1, 126.3, 49.3, 21.8.

N,N-Diphenylbenzamide (4x).^20b4x was prepared according to

the general procedure. Puriﬁcation by column chromatography (PE/

EA = 10:1): a white solid (120.2 mg, 44%), mp = 180.2−182.1 °C. ¹H

NMR (400 MHz, CDCl₃): δ 7.47 (d, J = 6.8 Hz, 2H), 7.29 (t, J = 8.0

Hz, 5H), 7.23−7.15 (m, 8H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

170.8, 144.1, 136.2, 130.3, 129.3, 129.2, 128.0, 127.6, 126.5.

4-Methoxy-N-phenylbenzamide (5a).^20b5a was prepared accord-

ing to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 15:1): a white solid (158.9 mg, 70%), mp = 177.7−179.1

N-Cyclohexylbenzamide (4p).³²4p was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

5:1): a white solid (182.8 mg, 90%), mp = 149.2−150.4 °C. ¹H NMR

(400 MHz, CDCl₃): δ 7.76−7.73 (m, 2H), 7.44 (t, J = 7.2 Hz, 1H),

7.37 (t, J = 7.6 Hz, 2H), 6.23 (brs, 1H), 3.99−3.90 (m, 1H), 2.00−

1.97 (m, 2H), 1.75−1.70 (m, 2H), 1.65−1.60 (m, 1H), 1.43−4.32

(m, 2H), 1.27−1.10 (m, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

166.7, 135.1, 131.2, 128.5, 126.9, 48.8, 33.2, 25.6, 25.0.

1

°C. H NMR (400 MHz, CDCl₃): δ 7.84 (d, J = 8.8 Hz, 2H), 7.76

(brs, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 7.2 Hz, 2H), 7.14 (t, J

= 7.2 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H). ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 165.4, 162.6, 138.2, 129.2, 129.0, 127.3, 124.5,

120.3, 114.1, 55.6.

N-Pentylbenzamide (4q).³³4q was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

5:1): a colorless oil (184.0 mg, 96%). ¹H NMR (400 MHz, CDCl₃): δ

7.76 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz,

2H), 6.78 (brs, 1H), 3.37 (q, J = 7.2 Hz, 2H), 1.60−1.53 (m, 2H),

1.32−1.24 (m, 4H), 0.86 (t, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 167.7, 134.8, 131.2, 128.4, 127.0, 40.1, 29.3, 29.2,

22.4, 14.0.

N-((1-Ethylpyrrolidin-2-yl)methyl)benzamide (4r). 4r was pre-

pared according to the general procedure. Puriﬁcation by column

chromatography (dichloromethane (DMC)/MeOH = 10:1): a yellow

oil (162.5 mg, 70%). ¹H NMR (400 MHz, CDCl₃): δ 7.84 (d, J = 6.8

Hz, 2H), 7.49−7.41 (m, 4H), 3.76−3.71 (m, 1H), 3.47−3.35 (m,

2H), 2.97−2.90 (m, 2H), 2.47−2.36 (m, 2H), 2.01−1.96 (m, 1H),

1.85−1.78 (m, 2H), 1.74−1.70 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 167.9, 134.3, 131.6, 128.7,

127.2, 63.8, 53.8, 49.2, 40.8, 28.2, 23.3, 13.2. HRMS (ESI-TOF) m/z:

[M + H]⁺Calcd for C₁₄H₂₁N₂O 233.1648; Found 233.1654.

4-Chloro-N-phenylbenzamide (5b).^16c5b was prepared according

to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 10:1): a white solid (171.4 mg, 74%), mp = 194.6−196.2

°C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.32 (brs, 1H), 7.98 (d, J =

8.4 Hz, 2H), 7.76 (d, J = 7.2 Hz, 2H), 7.62−7.60 (m, 2H), 7.36 (t, J =

7.6 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H). ¹³C{¹H} NMR (100 MHz,

DMSO-d₆): δ 164.5, 139.0, 136.4, 133.7, 129.7, 128.7, 128.5, 123.9,

120.4.

4-Iodo-N-(1-phenylethyl)benzamide (5c). 5c was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 10:1): a white solid (217.6 mg, 62%),

1

mp = 122.4−123.6 °C. H NMR (400 MHz, CDCl₃): δ 7.68 (d, J =

8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.32−7.26 (m, 4H), 7.23−7.19

(m, 1H), 6.27 (s, 1H), 2.27−5.20 (m, 1H), 1.52 (d, J = 6.8 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 165.9, 143.0, 137.9, 134.1,

2352

https://dx.doi.org/10.1021/acs.joc.0c02478

J. Org. Chem. 2021, 86, 2339−2358

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

128.9, 128.7, 127.7, 126.4, 98.5, 49.5, 21.8. HRMS (ESI-TOF) m/z:

[M + Na]⁺Calcd for C₁₅H₁₄INONa 374.0012; Found 374.0010.

2-Iodo-N-phenylbenzamide (5d).³⁵5d was prepared according to

the general procedure. Puriﬁcation by column chromatography (PE/

EA = 20:1): a white solid (171.2 mg, 53%), mp = 142.5−144.6 °C. ¹H

NMR (400 MHz, CDCl₃): δ 7.86 (d, J = 7.6 Hz, 1H), 7.75 (brs, 1H),

7.61 (d, J = 7.6 Hz, 2H), 7.47−7.44 (m, 1H), 7.36 (q, J = 7.2 Hz,

3H), 7.18−7.09 (m, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

167.5, 142.1, 140.0, 137.7, 131.5, 129.1, 128.5, 128.3, 124.9, 120.3,

92.6.

7.35−7.32 (m, 1H), 7.26−7.25 (m, 2H), 2.23 (s, 6H), 2.12 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 164.0, 152.2, 148.1, 137.2,

135.5, 134.6, 132.1, 131.0, 123.6, 120.1, 20.7, 15.0. HRMS (ESI-

TOF) m/z: [M + H]⁺Calcd for C₁₅H₁₇N₂O 241.1335; Found

241.1347.

N-Mesitylnicotinamide (5m).^19b5m was prepared according to

the general procedure. Puriﬁcation by column chromatography (PE/

EA = 5:1): a white solid (134.5 mg, 56%), mp = 177.2−178.6 °C. ¹H

NMR (400 MHz, CDCl₃): δ 8.97 (s, 1H), 8.58 (d, J = 4.8 Hz, 1H),

8.21 (s, 1H), 8.06−8.03 (m, 1H), 7.24−7.19 (m, 1H), 6.77 (s, 2H),

2.18 (s, 3H), 2.04 (s, 6H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

164.5, 152.1, 148.3, 137.2, 135.5, 135.3, 131.0, 130.4, 129.0, 123.6,

21.0, 18.2.

Indolin-1-yl(3,4,5-trimethoxyphenyl)methanone (5e).^19b5e was

prepared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 10:1): a white solid (297.5 mg, 95%), mp

1

N-(2,6-Diisopropylphenyl)nicotinamide (5n).^19b5n was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 5:1): a white solid (141.1 mg, 50%),

mp = 230.7−232.7 °C. ¹H NMR (400 MHz, CDCl₃): δ 9.09 (s, 1H),

8.71 (d, J = 3.2 Hz, 1H), 8.18 (dt, J = 8.0, 2.0 Hz, 1H), 7.93 (s, 1H),

7.37−7.32 (m, 2H), 7.23 (s, 1H), 7.21 (s, 1H), 3.10 (hept, J = 7.2 Hz,

2H), 1.18 (d, J = 6.8 Hz, 12H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

165.3, 152.5, 148.1, 146.5, 135.7, 131.0, 130.4, 128.8, 123.8, 123.7,

29.0, 23.7.

= 106.5−107.9 °C. H NMR (400 MHz, CDCl₃): δ 7.71 (brs, 1H),

7.21 (d, J = 7.2 Hz, 1H), 7.11 (brs, 1H), 7.02−6.98 (m, 1H), 6.77 (s,

2H), 4.10 (t, J = 7.6 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 6H), 3.11 (t, J =

8.4 Hz, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 168.6, 153.4,

142.5, 139.8, 132.5, 132.2, 127.3, 125.0, 124.0, 116.7, 104.5, 61.0,

56.3, 50.6, 28.1. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₁₈H₂₀NO₄314.1387; Found 314.1388.

4-Benzoylmorpholine (5f).^19a5f was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

1

Morpholino(pyridin-3-yl)methanone (5o).^19a5o was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 2:1): a yellow liquid (172.9 mg, 90%).

¹H NMR (400 MHz, CDCl₃): δ 8.65−8.63 (m, 2H), 7.73 (dt, J = 8.0,

2.4 Hz, 1H), 7.34 (dddd, J = 8.0, 4.8, 0.8 Hz, 1H), 3.74−3.43 (m,

8H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 167.8, 151.0, 148.0, 135.1,

131.2, 123.6, 66.8, 48.2, 42.7.

5:1): a white solid (168.2 mg, 88%), mp = 71.5−72.2 °C. H NMR

(400 MHz, CDCl₃): δ 7.42−7.39 (m, 5H), 3.73−3.45 (m, 8H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 170.3, 135.3, 129.8, 128.5,

127.0, 66.8, 48.2, 42.5.

N-(4-Fluorophenyl)furan-2-carboxamide (5g).²⁵5g was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 10:1): an oﬀ-white solid (160.1 mg,

1

Morpholino(pyridin-2-yl)methanone (5p).³⁷5p was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 2:1): a colorless liquid (182.5 mg,

95%). ¹H NMR (400 MHz, CDCl₃): δ 8.58 (d, J = 4.8 Hz, 1H), 7.82

(dt, J = 7.6, 2.8 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.38−7.33 (m,

1H), 3.81 (s, 4H), 3.69−3.67 (m, 4H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 167.4, 153.6, 148.2, 137.2, 124.6, 124.1, 67.0, 66.8, 47.7,

42.7.

78%), mp = 103.1−105.2 °C. H NMR (400 MHz, CDCl₃): δ 8.18

(s, 1H), 7.63−7.58 (m, 2H), 7.47−7.46 (m, 1H), 7.20 (qd, J = 3.6,

0.8 Hz, 1H), 7.05−7.00 (m, 2H), 6.52 (q, J = 1.6 Hz, 1H). ¹³C{¹H}

NMR (100 MHz, CDCl₃): δ 159.5 (d, J = 242 Hz), 156.2, 147.6,

144.3, 133.4 (d, J = 2.8 Hz), 121.8 (d, J = 7.9 Hz), 115.7 (d, J = 28

Hz), 115.3, 112.6.

N-(3,5-Dimethylphenyl)furan-2-carboxamide (5h).³⁶5h was

prepared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 10:1): a white solid (172.1 mg, 80%), mp

(5-Methylyrazin-2-yl)(morpholino)methanone (5q).^19a5q was

prepared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 2:1): a yellow liquid (188.5 mg, 91%). ¹H

NMR (400 MHz, CDCl₃): δ 8.79 (s, 1H), 8.33 (s, 1H), 3.74 (s, 4H),

3.63 (s, 4H), 2.55 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

165.4, 155.1, 145.8, 144.9, 142.1, 68.1, 66.9, 47.7, 42.9, 21.7.

Morpholino(naphthalen-2-yl)methanone (5r).^19a5r was pre-

pared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 2:1): a white solid (233.9 mg, 97%), mp =

1

= 88.6−89.2 °C. H NMR (400 MHz, CDCl₃): δ 8.09 (brs, 1H),

7.47−7.46 (m, 1H), 7.30 (s, 2H), 7.21−7.20 (m, 1H), 6.78 (s, 1H),

6.52 (q, J = 1.6 Hz, 1H), 2.30 (s, 6H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 156.1, 148.0, 144.2, 138.8, 137.3, 126.3, 117.8, 115.1,

112.6, 21.4.

Furan-2-yl(morpholino)methanone (5i).^19a5i was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 10:1): a yellow oil (157.5 mg, 87%).

¹H NMR (400 MHz, CDCl₃): δ 7.46 (dd, J = 2.0, 0.8 Hz, 1H), 7.01

(dd, J = 3.2, 0.8 Hz, 1H), 6.47 (dd, J = 3.6, 2.0 Hz, 1H), 3.79 (brs,

4H), 3.73−3.71 (m, 4H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

159.2, 147.8, 143.9, 116.9, 111.5, 67.0, 46.8.

1

101.3−102.2 °C. H NMR (400 MHz, CDCl₃): δ 7.90 (brs, 1H),

7.88−7.83 (m, 3H), 7.55−7.47 (m, 3H), 3.71−3.53 (m, 8H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 170.5, 133.8, 132.7, 132.6,

128.5, 128.4, 127.9, 127.2, 127.1, 126.8, 124.3, 66.9, 48.3, 42.7.

(3-Methylfuran-2-yl)(morpholino)methanone (5s). 5s was pre-

pared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 5:1): a yellow solid (130.7 mg, 67%), mp

N-Phenylnicotinamide (5j).¹⁸5j was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

1

10:1): a white solid (134.7 mg, 68%), mp = 119.2−120.4 °C. H

1

NMR (400 MHz, CDCl₃): δ 9.02−8.94 (m, 2H), 8.63 (t, J = 4.4 Hz,

1H), 8.12 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.32−7.27

(m, 3H), 7.15−7.11 (m, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

164.4, 152.1, 148.1, 137.7, 135.6, 131.0, 129.1, 125.1, 123.6, 120.9.

N-(2-Isopropylphenyl)nicotinamide (5k).^19b5k was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 5:1): a white solid (132.2 mg, 52%),

mp = 179.2−180.4 °C. ¹H NMR (400 MHz, CDCl₃): δ 9.13 (s, 1H),

8.78 (s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 8.03 (s, 1H), 7.64 (s, 1H),

7.47−7.43 (m, 2H), 7.30−7.21 (m, 2H), 1.45 (s, 9H). ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 164.1, 152.7, 147.9, 143.4, 135.5, 134.8, 130.7,

128.4, 127.1, 127.0, 126.9, 123.9, 34.8, 30.9.

= 46.2−47.5 °C. H NMR (400 MHz, CDCl₃): δ 7.25 (s, 1H), 6.24

(s, 1H), 3.65 (s, 8H), 2.20 (s, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 160.3, 142.5, 142.0, 127.9, 114.5, 66.9, 46.7, 44.4, 11.2.

HRMS (ESI-TOF) m/z: [M + Na]⁺Calcd for C₁₀H₁₃NO₃Na

218.0787; Found 218.0795.

Fenfuram (5t).^19a5t was prepared according to the general

procedure. Puriﬁcation by column chromatography (PE/EA = 5:1): a

yellow solid (106.6 mg, 53%), mp = 105.6−106.2 °C. ¹H NMR (400

MHz, CDCl₃): δ 7.56 (dd, J = 8.8, 1.2 Hz, 2H), 7.51 (brs, 1H), 7.33

(t, J = 7.6 Hz, 2H), 7.28 (d, J = 2.0 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H),

6.55 (d, J = 2.0 Hz, 1H), 2.62 (s, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 162.3, 158.0, 140.6, 137.9, 129.1, 124.5, 120.4, 115.9,

108.3, 13.7.

N-(3,4,5-Trimethylphenyl)nicotinamide (5l). 5l was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 5:1): a white solid (182.5 mg, 76%),

mp = 174.6−175.4 °C. ¹H NMR (400 MHz, CDCl₃): δ 9.05 (s, 1H),

8.66 (d, J = 4.8 Hz, 1H), 8.48 (brs, 1H), 8.16 (d, J = 8.0 Hz, 1H),

4-(2-Methyl-furan-3-carbonyl)-morpholine (5u).^19a5u was pre-

pared according to the general procedure. Puriﬁcation by column

1

chromatography (PE/EA = 5:1): a yellow oil (119.0 mg, 61%). H

NMR (400 MHz, CDCl₃): δ 7.24 (d, J = 2.0 Hz, 1H), 6.31(d, J = 2.0

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1

Hz, 1H), 3.67−3.62 (m, 8H), 2.37 (s, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 165.5, 153.9, 140.5, 115.3, 110.2, 67.1, 47.7, 42.6,

13.1.

10:1): a white solid (178.5 mg, 80%), mp = 153.6−155.1 °C. H

NMR (400 MHz, CDCl₃): δ 7.76 (d, J = 15.6 Hz, 2H), 7.66−7.64

(m, 2H), 7.50−7.48 (m, 2H), 7.36−7.32 (m, 5H), 7.12 (t, J = 7.2 Hz,

1H), 6.60 (d, J = 15.6 Hz, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

164.3, 142.5, 138.2, 134.7, 130.1, 129.2, 129.0, 128.1, 124.6, 121.0,

120.1.

N-Phenylthiophene-3-carboxamide (5v).^20a5v was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 5:1): a white solid (172.6 mg, 85%),

1

N-Benzylcinnamamide (6f).^16d6f was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

5:1): a white solid (218.2 mg, 92%), mp = 110.9−112.2 °C. ¹H NMR

(400 MHz, CDCl₃): δ 7.63 (d, J = 15.6 Hz, 1H), 7.44−7.41 (m, 2H),

7.31−7.26 (m, 8H), 6.61 (d, J = 9.6 Hz, 1H), 6.51−6.46 (m, 1H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 166.1, 141.2, 138.3, 134.8,

129.7, 128.8, 128.7, 127.9, 127.5, 120.69, 120.68, 43.8.

mp = 150.9−152.1 °C. H NMR (400 MHz, DMSO-d₆): δ 10.05

(brs, 1H), 8.35(t, J = 2.4 Hz, 1H), 7.75 (d, J = 7.6 Hz, 2H), 7.65−

7.64 (m, 2H), 7.35(t, J = 7.2 Hz, 2H), 7.09(t, J = 7.6 Hz, 1H).

¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 160.9, 139.0, 137.9, 129.7,

128.6, 127.2, 126.9, 123.6, 120.3.

5-Methyl-N-phenyloxazole-4-carboxamide (5w). 5w was pre-

pared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 5:1): a yellow liquid (185.9 mg, 92%), mp

= 84.7−87.2 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.75 (brs, 1H), 7.73

(s, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.13 (t, J =

7.2 Hz, 1H), 2.71 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

159.7, 154.3, 147.9, 137.7, 129.1, 129.0, 124.4, 119.8, 11.8. HRMS

(ESI-TOF) m/z: [M + Na]⁺calcd for C₁₁H₁₀N₂O₂Na 225.0634;

found 225.0641.

N-Hexylcinnamamide (6g).^16a6g was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

1

5:1): a white solid (201.3 mg, 87%), mp = 37.4−38.5 °C. H NMR

(400 MHz, CDCl₃): 7.62 (d, J = 15.6 Hz, 1H), 7.47−7.45 (m, 2H),

7.31−7.29 (m, 3H), 6.49 (d, J = 15.6 Hz, 1H), 6.36 (brs, 1H), 3.39−

3.34 (m, 2H), 1.56 (tt, J = 7.4, 7.4 Hz, 2H), 1.31−1.24 (m, 6H), 0.85

(t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 166.2,

140.6, 135.0, 129.6, 128.8, 127.8, 121.2, 39.9, 31.6, 29.7, 26.8, 22.6,

14.1.

2-Methyl-N-phenylthiazole-4-carboxamide (5x). 5x was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 5:1): a yellow solid (194.1 mg, 89%),

N-Benzyl-3-phenylpropiolamide (6h).^16d6h was prepared accord-

ing to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 5:1): a white solid (178.7 mg, 76%), mp = 110.2−111.5

1

mp = 113.5−114.2 °C. H NMR (400 MHz, CDCl₃): δ 9.20 (brs,

1H), 8.03 (s, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H),

7.13 (t, J = 7.6 Hz, 1H), 2.73 (s, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 166.2, 159.0, 149.8, 137.9, 129.1, 124.4, 123.7, 119.8, 19.2.

HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for C₁₁H₁₁N₂OS 219.0587;

Found 219.0594.

1

°C. H NMR (400 MHz, CDCl₃): 7.53−7.51 (m, 2H), 7.41−7.31

(m, 8H), 6.28 (brs, 1H), 4.54 (d, J = 6.0 Hz, 2H). ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 153.4, 137.4, 132.6, 130.2, 129.0, 128.6, 128.1,

127.9, 120.2, 85.3, 83.0, 44.1.

N-Phenyl-1H-benzo[d]imidazole-6-carboxamide (5y).³⁸5y was

prepared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 10:1): a purple solid (87.7 mg, 37%), mp

tert-Butyl (1-(benzylamino)-1-oxopropan-2-yl)carbamate

(6i).^16c6i was prepared according to the general procedure.

Puriﬁcation by column chromatography (PE/EA = 3:1): a white

1

= 274.6−277.5 °C. H NMR (400 MHz, DMSO-d₆): δ 12.75 (brs,

1

solid (250.3 mg, 90%), mp = 116.5−117.2 °C. H NMR (400 MHz,

1H), 10.22 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.86−7.80 (m, 3H),

7.68 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.09 (t, J = 7.2 Hz,

1H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 166.0, 144.1, 139.5,

139.4, 128.65, 128.62, 128.57, 123.4, 122.4, 122.0, 120.3, 110.1.

N,2-Diphenylacetamide (6a).^19a6a was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

CDCl₃): δ 7.29−7.20 (m, 5H), 7.16 (brs, 1H), 5.48 (brs, 1H), 4.39−

4.35 (m, 2H), 4.26 (t, J = 8.4 Hz, 1H), 1.38 (s, 9H), 1.32 (d, J = 7.2

Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 173.0, 155.6, 138.2,

128.6, 127.5, 127.3, 79.9, 50.1, 43.2, 28.3, 18.6. HPLC conditions:

DAICEL CHIRALCEL AD-H column (20% MeOH−CO₂, 1.5 mL/

min, 254 nm), t_R: 9.9 min (minor), 10.9 min (major).

1

10:1): a white solid (175.2 mg, 83%), mp = 116.5−117.2 °C. H

tert-Butyl (1-(benzylamino)-3-methyl-1-oxobutan-2-yl)-

carbamate (6j).^16c6j was prepared according to the general

procedure. Puriﬁcation by column chromatography (PE/EA = 5:1):

NMR (400 MHz, CDCl₃): δ 7.43−7.36 (m, 4H), 7.34−7.24 (m, 6H),

7.07 (t, J = 7.2 Hz, 1H), 3.71 (s, 2H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 169.3, 137.8, 134.6, 129.6, 129.3, 129.0, 127.7, 124.6,

120.0, 44.9.

1

a white solid (260.26 mg, 85%), mp = 120.4−121.2 °C. H NMR

(400 MHz, CDCl₃): δ 7.26−7.17 (m, 5H), 6.48 (brs, 1H), 5.09 (brs,

1H), 4.37 (t, J = 6.0 Hz, 2H), 3.87 (t, J = 6.8 Hz, 1H), 2.06 (brs, 1H),

1.34 (s, 9H), 0.88 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 171.7, 156.1, 138.2, 128.8,

127.8, 127.6, 60.2, 43.5, 30.9, 28.4, 19.5, 18.0. HPLC conditions:

DAICEL CHIRALCEL AD-H column (20% MeOH−CO₂, 1.5 mL/

min, 254 nm), t_R: 9.4 min (major), 10.8 min (minor).

Tetrahydro-pyran-4-carboxylic acid anilide (6b).^19a6b was

prepared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 5:1): a white solid (159.9 mg, 78%), mp =

152.7−154.6 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.51 (d, J = 7.6 Hz,

2H), 7.46 (brs, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.10 (t, J = 7.6 Hz, 1H),

4.05 (d, J = 11.6 Hz, 2H), 3.42 (td, J = 11.6, 2.0 Hz, 2H), 2.53−2.45

(m, 1H), 1.97−1.77 (m, 4H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

172.8, 137.9, 129.1, 124.5, 120.1, 67.3, 43.3, 29.3.

N-Benzylmandelamide (6k).⁴¹6k was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

2:1): a white solid (176.9 mg, 83%), mp = 101.4−102.3 °C. ¹H NMR

(400 MHz, CDCl₃): δ 7.37−7.24 (m, 8H), 7.16−7.14 (m, 2H), 6.65

(brs, 1H), 5.01 (s, 1H), 4.43−4.32 (m, 2H), 3.87 (d, J = 3.6 Hz, 1H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 172.4, 139.5, 137.8, 128.9,

128.8, 128.7, 127.7, 126.9, 74.2, 43.5. HPLC conditions: DAICEL

CHIRALCEL AD-H column (20% MeOH−CO₂, 1.5 mL/min, 254

nm), t_R: 11.7 min (minor), 12.4 min (major).

N-Phenylcyclohex-3-ene-1-carboxamide (6c).³⁹6c was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 20:1): a white solid (166.9 mg, 83%),

1

mp = 119.6−120.7 °C. H NMR (400 MHz, CDCl₃): δ 7.57 (brs,

1H), 7.53(d, J = 8.0 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.09 (t, J = 7.6

Hz, 1H), 5.76−5.70 (m, 2H), 2.50−2.50 (m, 1H), 2.40−2.35 (m,

1H), 2.29−2.24 (m, 1H), 2.15−2.09 (m,2H), 2.02−1.98 (m, 1H),

1.87−1.77 (m, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 174.5,

138.2, 129.0, 126.9, 125.3, 124.3, 120.0, 42.3, 28.2, 25.9, 24.67.

N-Pivaloylaniline (6d).^19a6d was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

N-Phenethyloleamide (7a).⁴²7a was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

10:1): a white solid (296.7 mg, 77%), mp = 42.3−43.2 °C. ¹H NMR

(400 MHz, CDCl₃): δ 7.19 (t, J = 7.2 Hz, 2H), 7.13−7.08 (m, 3H),

5.95 (brs, 1H), 5.27−5.24 (m, 2H), 3.39 (q, J = 7.2 Hz, 2H), 2.71 (t, J

= 7.2 Hz, 2H), 2.03 (t, J = 7.2 Hz, 2H), 1.95−1.90 (m, 3H), 2.03 (t, J

= 6.8 Hz, 2H), 1.21−1.18 (m, 21H), 0.81−0.78 (m, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃): δ 173.3, 139.0, 129.9, 129.7, 128.7, 128.5,

126.3, 40.6, 36.6, 35.7, 31.9, 29.73, 29.69, 29.63, 29.5, 29.33, 29.28,

29.24, 29.1, 27.2, 27.1, 25.8, 22.6, 14.1.

1

10:1): a white solid (131.1 mg, 74%), mp = 130.1−131.5 °C. H

NMR (400 MHz, CDCl₃): δ 7.52 (d, J = 7.6 Hz, 2H), 7.39 (brs, 1H),

7.31 (t, J = 7.2 Hz, 2H), 7.01 (t, J = 7.6 Hz, 1H), 1.31 (s, 9H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 176.7, 138.1, 129.0, 124.3,

120.1, 39.7, 27.7.

N-Phenylcinnamamide (6e).⁴⁰6e was prepared according to the

general procedure. Puriﬁcation by column chromatography (PE/EA =

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8-(3-Octyloxiran-2-yl)-N-phenethyloctanamide (7b).⁴³7b was

prepared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 15:1): a white solid (300.9 mg, 75%), mp

= 60.1−62.4 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.29 (t, J = 6.8 Hz,

2H), 7.23−7.17 (m, 3H), 5.57 (brs, 1H), 3.50 (q, J = 7.2 Hz, 2H),

2.90−2.87 (m, 2H), 2.80 (t, J = 6.8 Hz, 2H), 2.10 (t, J = 7.6 Hz, 2H),

1.60−1.26 (m, 26H), 0.88−0.85 (m, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 173.2, 139.1, 128.8, 128.7, 126.6, 57.32, 57.29, 40.6, 36.8,

35.8, 31.9, 29.63, 29.61, 29.4, 29.33, 29.30, 29.2, 27.9, 27.9, 26.69,

26.68, 25.8, 22.8, 14.2.

7.03 (m, 2H), 3.75 (s, 2H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ

168.6, 165.4, 139.7, 139.2, 139.1, 133.3, 129.1, 128.7, 128.6, 127.7,

123.6, 123.3, 120.3, 119.1, 43.1. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₂₁H₁₉N₂O₂331.1441; found 331.1464.

N-(3-(Methylamino)propyl)benzamide (C).⁴⁵C was prepared

according to the general procedure. Puriﬁcation by column

chromatography (DCM/MeOH = 10:1): a colorless liquid (163.3

mg, 85%). ¹H NMR (400 MHz, CDCl₃): δ 8.42 (brs, 1H), 7.76−7.74

(m, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 8.0 Hz, 2H), 4.00 (brs,

1H), 3.45 (q, J = 10.8, 5.2 Hz, 2H), 2.71 (t, J = 6.0 Hz, 2H), 2.38 (s,

3H), 1.76−1.70 (m, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

167.5, 134.4, 131.1, 128.3, 126.9, 49.8, 39.0, 35.6, 27.5.

8-(3-Octyloxiran-2-yl)-N-phenyloctanamide (7c). 7c was pre-

pared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 10:1): a white solid (265.1 mg, 71%), mp

= 79.4−80.6 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.50 (d, J = 7.6 Hz,

2H), 7.40 (brs, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.08 (t, J = 7.6 Hz, 1H),

2.93−2.88 (m, 2H), 2.34 (t, J = 7.2 Hz, 2H), 1.72−1.70 (m, 2H),

1.50−1.24 (m, 24H), 0.89−0.86 (m, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 171.6, 138.2, 129.1, 124.2, 119.9, 57.4, 37.8, 32.0, 31.6,

29.67, 29.65, 29.38, 29.34, 29.31, 29.2, 28.0, 27.9, 26.73, 26.71, 25.7,

22.8, 14.2. HRMS

N-(1-Hydroxypropan-2-yl)benzamide (D).⁴⁶D was prepared

according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 1:1): a pink solid (154.0 mg, 86%), mp

1

= 104.5−105.2 °C. H NMR (400 MHz, DMSO-d₆): δ 8.10 (d, J =

8.0 Hz, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.52−7.42 (m, 3H), 4.71 (brs,

1H), 4.07−4.00 (m, 1H), 3.47 (dd, J = 10.4, 5.6 Hz, 1H), 3.35 (dd, J

= 10.4, 6.4 Hz, 1H), 1.13 (d, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (100

MHz, DMSO-d₆): δ 165.9, 134.8, 131.0, 128.2, 127.3, 64.4, 47.3, 17.2.

N-(4-(2-(Dimethylamino)ethoxy)benzyl)-3,4,5-trimethoxybenza-

mide (E).²⁶E was prepared according to the general procedure.

Puriﬁcation by column chromatography (DCM/MeOH = 20:1): a

(ESI-TOF) m/z: [M + H]⁺calcd for C₂₄H₄₀NO₂374.3054; found

374.3058.

(E)-N-Phenethyldocos-13-enamide (7d). 7d was prepared accord-

ing to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 5:1): a white solid (357.5 mg, 81%), mp = 58.6−59.4 °C.

¹H NMR (400 MHz, CDCl₃): δ 7.29 (t, J = 6.8 Hz, 2H), 7.22−7.16

(m, 3H), 5.82 (brs, 1H), 5.34 (t, J = 4.8 Hz, 2H), 3.49 (dd, J = 12.8,

6.8 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.11 (t, J = 7.6 Hz, 2H), 2.04−

1.99 (m, 4H), 1.59−1.55 (m, 2H), 1.35−1.25 (m, 28H), 0.88 (t, J =

6.4 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 173.3, 139.0,

129.91, 129.88, 128.8, 128.6, 126.5, 40.6, 36.8, 35.8, 32.7, 31.9, 29.82,

29.81, 29.75, 29.68, 29.61, 29.56, 29.43, 29.36, 29.27, 29.21, 29.17,

27.2, 25.8, 25.1, 22.7, 14.1. HRMS (ESI-TOF) m/z: [M + Na]⁺calcd

for C₃₀H₅₁NONa 464.3863; found 464.3866.

1

colorless liquid (314.4 mg, 81%). H NMR (400 MHz, CDCl₃): δ

7.23 (d, J = 8.4 Hz, 2H), 7.01 (s, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.62

(m, 1H), 4.51 (d, J = 5.6 Hz, 2H), 4.04 (t, J = 5.6 Hz, 2H), 3.84 (s,

9H), 2.04 (t, J = 5.6 Hz, 2H), 2.33 (s, 6H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 167.1, 158.3, 153.2, 140.9, 130.6, 129.9, 129.3,

114.8, 104.5, 65.9, 61.0, 58.2, 56.4, 45.8, 43.7.

N-(4-(2-(Dimethylamino)ethoxy)benzyl)-3,4-dimethoxybenza-

mide (F).²⁶F was prepared according to the general procedure.

Puriﬁcation by column chromatography (DCM/MeOH = 30:1): a

1

colorless liquid (279.4 mg, 78%). H NMR (400 MHz, CDCl₃): δ

7.41 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 6.4, 2.0 Hz, 1H), 7.19 (d, J =

8.8 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 4.48

(d, J = 5.6 Hz, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.84 (d, J = 4.0 Hz, 6H),

2.68 (t, J = 6.0 Hz, 2H), 2.29 (s, 6H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 166.9, 158.2, 151.7, 148.9, 130.7, 129.2, 127.1, 119.5,

114.7, 110.7, 110.2, 65.9, 58.2, 55.9, 45.8, 43.5.

Computational Details. All OF the DFT calculations were

performed using the Gaussian 09 program⁴⁷and the geometries were

fully optimized at the solution phase (toluene as solvent) with the

SMD solvation model.⁴⁸The B3LYP⁴⁹functional with SDD⁵⁰basis

set for the Mn atom and 6-31G(d,p) basis set for the other atoms was

used for geometry optimization involved in the model reaction. After

the structural optimizations for all of the stationary points, frequency

calculations at the same level of theory were carried out to identify all

of the stationary points as minima (zero imaginary frequency) or

transition state (only one frequency), and to provide corrections for

free energies. To obtain a more precise energy, The B3LYP-D3⁵¹

functional with SDD basis set for Mn atom and 6-311+G(d,p) basis

set for the other atoms was used to calculate the solvation single point

energies to provide more accurate energy information.

(9Z,12E)-N-Phenethyloctadeca-9,12-dienamide (7e). 7e was

prepared according to the general procedure. Puriﬁcation by column

1

chromatography (PE/EA = 10:1): a yellow oil (256.8 mg, 67%). H

NMR (400 MHz, CDCl₃): δ 7.30 (t, J = 7.6 Hz, 2H), 7.24−7.17 (m,

3H), 5.57 (brs, 1H), 5.39−5.31 (m, 4H), 3.51 (q, J = 6.8 Hz, 2H),

2.83−2.75 (m, 4H), 2.11 (t, J = 7.6 Hz, 2H), 2.07−2.02 (m, 4H),

1.60−1.56 (m, 2H), 1.37−1.28 (m, 14H), 0.90−0.87 (m, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 173.3, 139.0, 130.3, 130.1,

128.8, 128.7, 128.1, 128.0, 126.6, 40.6, 36.9, 35.8, 31.6, 29.7, 29.4,

29.4, 29.3, 29.2, 27.3, 25.8, 25.7, 25.0, 22.7, 14.2. HRMS (ESI-TOF)

m/z: [M + Na]⁺calcd for C₂₆H₄₁NONa 406.3080; found 406.3086.

N-Phenethylundec-10-enamide (7f).⁴⁴7f was prepared according

to the general procedure. Puriﬁcation by column chromatography

(PE/EA = 10:1): a white solid (247.1 mg, 86%), mp = 47.5−48.2 °C.

¹H NMR (400 MHz, CDCl₃): δ 7.29 (t, J = 6.8 Hz, 2H), 7.23−7.17

(m, 3H), 5.82−5.74(m, 2H), 4.94 (qq, J = 12.0, 1.6 Hz, 2H), 3.49 (q,

J = 6.0 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.11 (t, J = 7.2 Hz, 2H),

2.05−2.00 (m, 2H), 1.59−1.56 (m, 2H), 1.38−1.26 (m, 10H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 173.3, 139.1, 139.0, 128.7,

128.6, 126.4, 114.2, 40.6, 36.8, 35.7, 33.8, 29.33, 29.27, 29.1, 28.9,

25.8, 24.7.

ASSOCIATED CONTENT

■

sı

* Supporting Information

Methyl 4-(2-oxo-2-(phenylamino)ethyl)benzoate (A).^19bA was

prepared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 2:1): a white solid (177.6 mg, 66%), mp =

116.5−117.9 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.03 (d, J = 8.0 Hz,

2H), 7.42 (t, J = 8.4 Hz, 4H), 7.30−7.26 (m, 3H), 7.10 (t, J = 7.2 Hz,

1H), 3.92 (s, 3H), 3.76 (s, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃):

δ 168.3, 166.9, 139.7, 137.6, 130.4, 129.6, 129.1, 127.5, 124.8, 120.1,

52.3, 44.8.

4-(2-Oxo-2-(phenylamino)ethyl)-N-phenylbenzamide (B). B was

prepared according to the general procedure. Puriﬁcation by column

chromatography (PE/EA = 1:1): a white solid (92.4 mg, 28%), mp =

165.4−168.2 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.20 (d, J = 8.0

Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.60 (d, J

= 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.37−7.28 (m, 4H), 7.11−

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02478.

NMR spectra and X-ray crystallographic data of the

manganese complexes; NMR spectra of the amides;

HPLC spectra for 6i,k and UV−vis and IR spectra for

mechanism; kinetic studies for reaction order; and DFT

calculations data (PDF)

Accession Codes

CCDC 1961734, 1965826, and 1965828 contain the

supplementary crystallographic data for this paper. These

data can be obtained free of charge via www.ccdc.cam.ac.uk/

2355

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J. Org. Chem. 2021, 86, 2339−2358

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

data_request/cif, or by emailing data_request@ccdc.cam.ac.

uk, or by contacting The Cambridge Crystallographic Data

Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44

1223 336033.

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AUTHOR INFORMATION

■

Corresponding Authors

Donghui Wei − College of Chemistry, Center of

Computational Chemistry, Zhengzhou University, Zhengzhou

450001, People’s Republic of China; orcid.org/0000-

0003-2820-282X; Email: donghuiwei@zzu.edu.cn

Ning Liu − School of Chemistry and Chemical Engineering,

Key Laboratory for Green Processing of Chemical Engineering

of Xinjiang Bingtuan, Shihezi University, Shihezi, Xinjiang

832003, People’s Republic of China; orcid.org/0000-

0001-7299-0400; Phone: (+0086)-0993-205-7277;

Email: ningliu@shzu.edu.cn, ninglau@163.com;

Fax: (+0086)-0993-205-7270

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Authors

Zhengqiang Fu − School of Chemistry and Chemical

Engineering, Key Laboratory for Green Processing of

Chemical Engineering of Xinjiang Bingtuan, Shihezi

University, Shihezi, Xinjiang 832003, People’s Republic of

China

Xinghua Wang − College of Chemistry, Center of

Computational Chemistry, Zhengzhou University, Zhengzhou

450001, People’s Republic of China

Sheng Tao − School of Chemistry and Chemical Engineering,

Key Laboratory for Green Processing of Chemical Engineering

of Xinjiang Bingtuan, Shihezi University, Shihezi, Xinjiang

832003, People’s Republic of China

Qingqing Bu − School of Chemistry and Chemical

Engineering, Key Laboratory for Green Processing of

Chemical Engineering of Xinjiang Bingtuan, Shihezi

University, Shihezi, Xinjiang 832003, People’s Republic of

China

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02478

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Author Contributions

Z.F. and N.L. performed the majority of experiments and

drafted the paper. X.W. and D.W. contributed the theoretical

calculations. S.T. provided his assistance in the single crystal X-

ray diﬀraction. Q.B. proposed valuable advice for improving

the paper. All authors discussed the results and commented on

the manuscript.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank the support from the National Natural Science

Foundation of China (21868033), Xinjiang Bingtuan Young

and Middle-Aged Leading Scientists Program (2020CB027),

Shihezi Young and Middle-Aged Leading Scientists Program

(2019RC01), International Partnership Program of Shihezi

University (GJHZ201908), and Double First-Class Program of

Shihezi University (SHYL-ZD201801). We thank Ji-Xing Zhao

for his assistance with the single crystal X-ray diﬀraction,

located at the Analysis and Testing Center, Shihezi University.

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https://dx.doi.org/10.1021/acs.joc.0c02478

J. Org. Chem. 2021, 86, 2339−2358

Article Doi

Manganese Catalyzed Direct Amidation of Esters with Amines

DOI: 10.1021/acs.joc.0c02478

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Article abstract of DOI:10.1021/acs.joc.0c02478

Full text of DOI:10.1021/acs.joc.0c02478

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