Copper-Catalyzed Regioselective Oxidative Cycloamidation of α-[(β-Dimethylamino)propenoyl]-Alkylamides: Synthetic Route to Substituted Pyrrolidine-2,4-diones

Title: Copper-Catalyzed Regioselective Oxidative Cycloamidation of α-

[(β-Dimethylamino)propenoyl]-Alkylamides: Synthetic Route to

Substituted Pyrrolidine-2,4-diones

Authors: Jingwen Yuan, Bhujanga Rao chitturi, YONGJIU liang, RUI

ZHANG, qian zhang, liman hou, and Dewen Dong

This manuscript has been accepted after peer review and appears as an

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the VoR from the journal website shown below when it is published

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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801237

Link to VoR: http://dx.doi.org/10.1002/adsc.201801237

10.1002/adsc.201801237

Advanced Synthesis & Catalysis

FULL PAPER

DOI: 10.1002/adsc.201((will be filled in by the editorial staff))

Copper-Catalyzed Regioselective Oxidative Cycloamidation of

α-[(β-Dimethylamino)propenoyl]-Alkylamides: Synthetic Route

to Substituted Pyrrolidine-2,4-diones

Jingwen Yuan,^a,bChitturi Bhujanga Rao,^aYongjiu Liang,^aRui Zhang,^a,* Qian Zhang,^a

Liman Hou,^aand Dewen Dong^a,*

a

Key Laboratory of High Performance Synthetic Rubber and its Composites, Changchun Institute of Applied Chemistry,

Chinese Academy of Sciences, Changchun, 130022, China

University of the Chinese Academy of Sciences, Beijing, 100049, China

b

Fax: (+86)-431-85262740; phone: (+86)-431-85262992; (+86)-431-85262676

Email Address: ariel@ciac.ac.cn; dwdong@ciac.ac.cn

Received: ((will be filled in by the editorial staff))

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.

Abstract. An intramolecular oxidative amidation of varied efficient protocol for the construction of C–N bond, but

α-[(β-dimethylamino)propenoyl]-alkylamides catalyzed by also a straightforward synthetic route to densely substituted

copper(II) bromide in the presence of PIFA and TFA has pyrrolidine-2,4-diones.

been described. This process features mild reaction

conditions, simple execution, good yields, high regio-

selectivity, and thereby, provides not only a facile and

Keywords: Amidation; C–N bond formation; Copper;

Cyclization; Hypervalent iodine reagents; Radical reactions

Introduction

Pyrrolidine-2,4-diones, also known as tetramic acids,

constitute the key core units in many naturally

occurring products and synthetic compounds along

with remarkable and diverse biological functions,

such as antibiotic and antiviral activity.^[1,2]The

pharmacological importance of pyrrolidine-2,4-dione

derivatives and their utility in organic transformations

have intrigued researchers in search of efficient

synthesis of such five-membered aza-heterocycles.^[3,4]

So far, extensive work has generated a variety of

synthetic approaches by the construction of C–N or

C–C bond through: 1) intramolecular aminolysis of γ-

amino esters,^[5]2) Dieckmann cyclization of N-acyl-

α-amino esters,^[6]3) nucleophilic cyclization of γ-

bromo β-ketocarboxamides,^[7]4) acylation of the

pyrrolidine-2,4-dione ring at C-3,^[8]5) Lewis acid or

base-induced ring-expansion of β-lactams,^[9]and 6)

ring-contraction of diketopiperazines.^[10]Recently,

Liu and coworkers reported a regioselective synthesis

of pyrrolidine-2,4-diones via the intramolecular aza-

anti-Michael addition of amides to enones, depending

on the β-substituent R on the enone moiety and/or the

substituent R¹on the remote amide nitrogen atom

(Scheme 1a).^[11]Although it seems somewhat difficult

to precisely control the exact addition mode in certain

cases, the polarity-reversible conjugated addition

indeed provided an alternative direct route to the

synthesis of pyrrolidine-2,4-diones.

Scheme 1. Cyclization of α-alkenoyl alkylamides

Over the past decades, hypervalent iodine reagents

have emerged as a class of efficient, inexpensive and

environmental benign oxidants,^[12]which have been

successfully used in various oxidative reactions of

amides to construct N–X (X = C, N, S, O) linkages

through N-acyl nitrenium ion intermediates.^[13]

During the course of our studies on the synthesis of

heterocycles from β-oxo amide derivatives, we

investigated the reaction behaviors of a variety of

functionalized amides in the presence of different

hypervalent iodine reagents, and achieved efficient

1

10.1002/adsc.201801237

Advanced Synthesis & Catalysis

synthesis of substituted pyrrolin-4-ones,^[14]benzo[d]-

thiazoles,^[15]isothiazol-3(2H)-ones,^[16]spiro-fused

pyrazolin-5-one N-oxides,^[17]isoxazol-3(2H)-ones,^[18]

and 2,5-dihydrofurans,^[19]respectively. Among these

inter- or intramolecular oxidative reactions, it is

worth noting that the selective N–X or O–X bond

formation occurred during the transformation of

amides, which is intimately dependent on the

chemical structures of the substrates and/or the

reaction conditions. Actually, it is one of the most

challenging issues to control the bond formation of

N–X or O–X in a chemoselective manner by tuning

the reaction conditions in the use of amides in organic

synthesis.^[20]

diones involving a regioselective intramolecular

amidation under very mild conditions (Scheme 1c).

Results and Discussion

A series of α-[β-(dimethylamino)propenoyl]-alkyl

amides 1 were prepared according to our previously

reported procedure from commercially available β-

oxo amides in good yields.^[21,22]Then, we selected 5-

(dimethylamino)-2,2-diethyl-3-oxo-N-phenylpent-4-

enamide 1a as a model compound to initiate our

study. The reaction of 1a and PIDA (2.0 equiv) was

.

performed in the presence of BF₃OEt₂(0.3 equiv)

and CuBr₂(0.1 equiv) in dichloromethane (DCM) at

room temperature. As indicated by TLC results, the

reaction was completed to form a predominant

product within 0.5 h, and had no significant change

even by prolonging the reaction time to 24 h (Table 1,

entry 1). The product was isolated and characterized

as dihydrofuran-3(2H)-one 2a on the basis of its

spectral and analytical data. In sharp contrast, when

phenyliodine(III) bis(trifluoroacetate) (PIFA), a more

potent oxidant than PIDA, was employed, the

reaction of 1a delivered a new product, which was

characterized as pyrrolidine-2,4-dione 3a based on its

spectral and analytical data (Table 1, entry 2).

Most recently, we found that α-[β-(dimethylamino)

propenoyl]-alkylamides underwent direct regio-

selective cyclization in the presence of phenyliodine-

(III) diacetate (PIDA) and boron trifluoride diethyl

.

etherate (BF₃OEt₂) to give dihydrofuran-3(2H)-ones

(Scheme 1b).^[21]Inspired by these results, we set out

to explore if intramolecular heterocylization of such

substrates might take place in different chemo- and/or

regioselective manner under appropriate conditions.

As part of our continued interest in the oxidation of

functionalized amides mediated by hypervalent

iodine(III) reagents, herein, we wish to report a novel

and efficient synthesis of substituted pyrrolidine-2,4-

Table 1. Selected assays performed on α-[β-(dimethylamino)propenoyl] alkylamide 1a ^[a]

.

Yield^[b][%]

Entry

Oxidant

Additive

[equiv]

Catalyst

[equiv]

CuBr₂

Solvent

Time

[h]

24

12

24

12

24

12

[equiv]

2a

3a

.

1

PIDA (2.0)

PIFA (2.0)

PIFA (1.5)

PIFA (2.5)

PIFA (2.0)

BF₃OEt₂(0.3)

CH₂Cl₂

CH₃CN

toluene

THF

64

0

2

BF₃.OEt₂(0.3)

TFA (0.3)

TFA (1.0)

TFA (2.0)

CuBr₂

55

62

77

81

0

3

CuBr₂

0

4

CuBr₂

0

5

CuBr₂

0

6

52

7

CuBr₂

__

mixture

8

9^[c]

10^[c]

11

12

13

14

15

16

17

18

Cu(OAc)₂

CuSO₄

CuCl₂

CuBr

0

5

trace

64

59

41

72

54

38

22

0

CuI

0

ZnCl₂

FeCl₃

0

CuBr₂

0

14

51

[c]

^[a]Reagents and conditions: 1a (1.0 mmol), catalyst (0.1 mmol), solvent (10.0 mL), rt. ^[b]Isolated yield of 2a or 3a.

Unidentified byproducts formed.

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Advanced Synthesis & Catalysis

Next, by fixing PIFA as the oxidant, we examined

hypervalent iodine reagent-mediated reactions.^[13g,20b]

Further experiments demonstrated that the modified

reaction conditions with the decrease of TFA to 0.5

equivalent were suitable for cyclopropyl-amides 1p,

1q and α-mono- or α,α-diallyl acetamides 1r-t to give

the corresponding pyrrolidine-2,4-diones 3p-t in

moderate to good yields. Therefore, we developed a

protocol for the operationally simple and efficient

construction of N–C bond in a regioselective manner,

and provied an alternative straightforward synthetic

route to densely substituted pyrrolidine-2,4-diones

from varied α-[β-(dimethylamino)propenoyl]-alkyl

amides 1.

the effect of additives, loading amount of additives

and PIFA, catalysts, and solvents on the reaction of

1a aiming to optimize the yield of 3a, and some

results are summarized in Table 1. It was observed

that trifluoroacetic acid (TFA) was a more efficient

.

additive than BF₃OEt₂to promote the reaction (entry

3), and the yield of 3a was significantly improved by

the increase of TFA from 0.3 to 2.0 equivalents

(entries 3-5). Notably, only product 2a was obtained

by decreasing PIFA to 1.5 equivalents (entry 6),

whereas a complex mixture was formed by increasing

PIFA to 2.5 equivalents (entry 7), namely the loading

amount of PIFA had a significant influence on the

transformation of 1a. As indicated by TLC, the

reaction of 1a with PIFA and TFA in the absence of

CuBr₂proceeded quickly to form 2a (<10 min),

however, it turned into a complex mixture after

prolonging the reaction time to 12 h (entry 8). These

results implied that a catalyst, such as CuBr₂, was

essential for the conversion of 1a to 3a. Further

experiments disclosed that CuBr₂was the most

effective one among the tested catalysts, including

Cu(OAc)₂, CuSO₄, CuCl₂, CuBr, CuI, ZnCl₂and

FeCl₃(entries 5, 9-15). Disappointingly, screening of

various solvents revealed that the employment of

acetonitrile or toluene gave poor yield of 3a (entries

16 and 17), and even no desired product 3a was

detected in tetrahydrofuran (entry 18). Therefore, the

optimal reaction conditions were obtained when 1a

was treated with PIFA (2.0 equiv) and TFA (2.0

equiv) in the presence of CuBr₂(0.1 equiv) in DCM

at room temperature, whereby the yield of 3a reached

81% (entry 5).

With the optimal reaction conditions in hand, we

explored the scope and limitation of this oxidative

cycloamidation reaction with a variety of α-[β-

(dimethylamino)propenoyl]-alkylamides 1. As shown

in Scheme 2, the reactions of alkylamides 1b-j

bearing diethyl or di-n-butyl substituents at α-position

proceeded smoothly to afford the corresponding

pyrrolidine-2,4-diones 3b-j in moderate to good

yields. It is worth noting that the electron-deficient Cl

(1c and 1h) and electron-rich OMe groups (1d and 1g)

on the N-phenyl ring were well tolerated under the

reaction conditions. For alkylamides 1e-1g, a

prolonged reaction time was required to complete the

oxidative process, which might stem from the steric

hindrance effect of the substituent on the N-phenyl

ring.^[13i,23]It should be mentioned that the structure of

3c was established by X-ray diffraction analysis as

shown in Scheme 2.

The versatility of this oxidative transformation was

further evaluated by performing the reactions of

cyclopentylamides 1k-o under identical conditions,

and the corresponding spiro-fused pyrrolidine-2,4-

diones 3k-o were obtained in moderate to high yields.

In comparison to those N-arylamides 1k-n, the

reaction of N-alkylamide 1o proceeded sluggishly,

which is attributed to the electron effect of amide

motifs. Actually, the difference of reactivity between

N-aryl and N-alkyl amides had been reported in some

Scheme 2. Reaction Scope. Reaction conditions for 3a-o:

1 (1.0 mmol), PIFA (2.0 mmol), TFA (2.0 mmol), CuBr₂

(0.1 mmol), DCM (10.0 mL), rt. Modified reaction

conditions for 3p-t: 1 (1.0 mmol), PIFA (2.0 mmol), TFA

(0.5 mmol), CuBr₂(0.1 mmol), DCM (10.0 mL), rt.

Reaction time and Isolated yields of 3 are given.

In contrast with our previous work wherein

dihydrofuran-3(2H)-ones were obtained from α-[β-

(dimethylamino)propenoyl]-alkylamides 1 through an

intramolecular O–C bond formation,^[21]we achieved

3

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Advanced Synthesis & Catalysis

the synthesis of pyrrolidine-2,4-diones from the same

substrates via an intramolecular N–C bond formation

in the present work. The exact origin of such

selectivity between N–C and O–C bond formation is

unclear,^[20]but the oxidativity of different hypervalent

iodine reagents did play a critical role to switch the

reaction pathway, and the catalysis of transition-metal

halides is of crucial importance for the N–C bond

formation. To gain insight into the mechanism of the

intramolecular oxidative amidation, a set of control

experiments were conducted as shown in Scheme 3.

In a separate experiment, 1a was subjected to the

identical conditions as described in entry 5, Table 1

for 0.1 h, and then quenched with water, which

delivered 2a in 75% yield (Scheme 3a). Subsequently,

the reaction of 2a was performed with PIFA (1.0

equiv) and TFA (2.0 equiv) in the presence of CuBr₂

(0.1 equiv) under ambient air conditions, and 3a was

obtained in 61% yield (Scheme 3b). In another

separate experiment, it was observed that the

treatment of 1a with PIFA, TFA and CuBr₂under

argon atmosphere afforded 3a in 79% yield (Scheme

3c). It is worth noting that the addition of 2,6-di-tert-

butyl-hydroxytoluene (BHT) inhibited the reaction of

2a, wherein no desired product 3a was formed and 2a

was recovered in 82% yield (Scheme 3d). These

results reveal that 2a is only a relatively stable

intermediate during the conversion from 1a to 3a, and

the oxidative transformation is associated with a free

radical process in which oxygen (air) is not essential.

and 933.1, which could be easily assigned to the 2p^3/2

binding energies of Cu^Iand Cu^II, respectively.^[24]In

contrast, the signal at 933.1 disappeared for the off-

white residue recovered at the final reaction stage.

XPS analyses clearly demonstrated that the redox

state of Cu^IIspecies changed during the oxidative

transformation process, and the formation of Cu^I

suggested that product 3 might be derived from the

reductive elimination of a Cu^IIIintermediate.^[25]

Figure 1. XPS Spectra of the insoluble residues recovered

from the reaction mixture at different reaction times: (a)

0.5 h; and (b) 12 h.

On the basis of the above experimental results

together with our previous work,^[21]a mechanism for

the synthesis of pyrrolidine-2,4-diones 3 is proposed

as depicted in Scheme 4. Mediated by PIFA, α-[β-

(dimethylamino)propenoyl]-alkylamide 1 is quickly

converted into a fairly stable dihydrofuran-3(2H)-one

2,^[21]which is further oxidized by PIFA via a SET

process to generate a cation radical A and iodanyl

radical B.^[26,27]The cation A is captured by TFA to

afford intermediate C,^[13c-f,28]acompanied by a ring-

opening reaction in the presence of transition metal

halide to give a radical D.^[29,30]The latter couples with

B forms intermediate E, which undergoes cyclization

to generate intermediate F,^[31]followed by a

dehydrohalogenation to afford an intervening triflate

G. The hydrolysis of G during workup furnishes the

final product, pyrrolidine-2,4-dione 3, through

intermediate H.^[13e,f]When transition metal is copper,

intermediate F can be generated via another pathway,

namely, the ring-opening reaction of C ocurrs to give

a chelated Cu^IIspecies I,^[25]followed by an oxidative

cyclization to form a metallacycle J, and the

reductive elimination of J leads to intermediate

F.^[25,32]During this process, the oxidation of the

released Cu^Iby PIFA or iodanyl radical B to Cu^II

brings reaction to the next catalytic cycle,^[32,27d]and

hence the copper-involved redox cycle further

facilitates the oxidative cycloamidation of 1 to 3.

Scheme 3. Control experiments

Conclusions

To get further information, the reaction of 1a and

PIFA was conducted in the presence of TFA and

CuBr₂under argon atmosphere, and the precipitates

recovered from the reaction mixture at different

reaction time were investigated by means of X-ray

photoelectron spectroscopy (XPS). As illustrated in

Figure 1, the black residue recovered at the initial

reaction stage showed characteristic signals at 931.6

In summary, we have described herein an

intramolecular oxidative amidation of varied α-[(β-

dimethylamino)propenoyl]-alkylamides 1 catalyzed

by copper(II) bromide in the presence of PIFA and

TFA. This newly developed reaction features mild

conditions, simple execution, wide functional group

4

10.1002/adsc.201801237

Advanced Synthesis & Catalysis

tolerance, and good yields, and thereby, provides not

only an efficient protocol for the construction of N–C

bond in a regioselective manner, but also a facile,

novel and straightforward synthetic route to densely

substituted pyrrolidine-2,4-diones. Further studies on

the mechanism involved in the reactions and the

utilization and extension of the scope of the protocol

are currently underway in our laboratory.

Scheme 4. Plausible reaction mechanism.

silica gel-coated plates. The products were isolated by flash

column chromatography on silica gel (300−400 mesh).

Experimental Section

General

General procedure for the synthesis of 2a:To a well-

stirred mixture of PIDA (644 mg, 2.0 mmol), boron

.

All reagents were purchased from commercial sources and trifluoride diethyl etherate (BF₃OEt₂, 0.038 mL, 0.3 mmol),

used without treatment, unless otherwise indicated. ¹H and CuBr₂(23 mg, 0.1 mmol) in CH₂Cl₂(10 mL) was

o

NMR and ¹³C NMR spectra were recorded at 25 C at 300 added α-[(β-dimethylamino)propenoyl]-alkylamide 1 (1.0

MHz (or 400 MHz) and 100 MHz, respectively, with TMS mmol). The reaction mixture was kept at room temperature

as internal standard. IR spectra (KBr) were recorded on a under stirring for 24 h. The resulting mixture was poured

FTIR-spectrophotometer in the range of 400-4000 cm^-1. into saturated aqueous NaCl (50 mL) and extracted with

High resolution mass spectra (ESI/HRMS) were recorded CH₂Cl₂(3 × 20 mL). The combined organic phase was

on a LTQ Orbitrap Velos Pro mass spectrometer. Melting washed with water, dried over anhydrous MgSO₄, filtered,

points were determined on a TECH X-4 micro-melting and evaporated in vacuo. The crude product was purified

point apparatus. The X-ray photoelectron spectroscopic by column chromatography (silica gel, petroleum ether/

(XPS) analysis was measured using Thermo ESCALAB ethyl acetate = 7:1) to give 2a as a pale yellow solid (183

250. All reactions were monitored by TLC with GF254 mg, 64%).

5

10.1002/adsc.201801237

Advanced Synthesis & Catalysis

General procedure for the synthesis of 3a-o: To a well- MHz, CDCl₃): δ 207.7, 174.0, 163.1, 136.2, 134.5, 129.7,

stirred mixture of PIFA (860 mg, 2.0 mmol), TFA (0.152 123.2, 68.3, 57.9, 37.4, 36.5, 28.1, 20.9, 9.2, 9.0; IR (KBr):

mL, 2.0 mmol), and CuBr₂(23 mg, 0.1 mmol) in CH₂Cl₂3040, 2978, 2968, 2939, 2928, 2881, 1763, 1680, 1662,

(10 mL) was added α-[(β-dimethylamino)propenoyl]- 1608, 1588, 1518, 1493, 1458, 1433, 1414, 1400, 1393,

alkylamide 1 (1.0 mmol). The reaction mixture was kept at 1344, 1301, 1256, 847 cm^-1. HRMS (ESI) m/z: [M + Na]⁺

room temperature under stirring until the completion of the Calcd for C₁₈H₂₄N₂O₃Na 339.1679, Found 339.1667.

reaction as indicated by TLC. The resulting mixture was

1-(4-Chlorophenyl)-4,4-diethyl-N,N-dimethyl-3,5-dioxo-

poured into saturated aqueous NaCl (50 mL) and extracted

pyrrolidine-2-carboxamide (3c): 246 mg, 73% yield;

with CH₂Cl₂(3 × 20 mL). The combined organic phase

o

1

white solid; mp 172-173 C; H NMR (300 MHz, CDCl₃):

δ 7.44 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 9.0 Hz, 2H), 5.42 (s,

1H), 3.32 (s, 3H), 2.98 (s, 3H), 1.81-1.89 (m, 4H), 0.91 (t, J

= 7.5 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃): δ 206.9, 174.1, 162.7, 135.7, 131.6, 129.2,

124.2, 68.1, 58.0, 37.5, 36.5, 28.1, 9.2, 8.9; IR (KBr): 3093,

3057, 3038, 2972, 2937, 2882, 1764, 1686, 1661, 1594,

1497, 1458, 1434, 1417, 1401, 1390, 1342, 1301, 1256,

853, 740 cm^-1. HRMS (ESI) m/z: [M + Na]⁺Calcd for

C₁₇H₂₁ClN₂O₃Na 359.1133, Found 359.1118.

was washed with water, dried over anhydrous MgSO₄,

filtered, and evaporated in vacuo. The crude product was

purified by column chromatography on silica gel with

petroleum ether/ethyl acetate as the eluent to give the

corresponding product 3a-o.

General procedure for the synthesis of 3p-t: To a well-

stirred mixture of PIFA (860 mg, 2.0 mmol), TFA (0.038

mL, 0.5 mmol), and CuBr₂(23 mg, 0.1 mmol) in CH₂Cl₂

(10 mL) was added α-[(β-dimethylamino)propenoyl]-alkyl

amide 1 (1.0 mmol). The reaction mixture was kept at room X-ray Crystal Data for 3c: white crystal, M = 336.81,

temperature under stirring until the completion of the orthorhombic, Pbca, a = 15.199(2) Å, b = 8.9579(13) Å, c

reaction as indicated by TLC. The resulting mixture was = 25.874(4) Å, α = 90.00°, β = 90.00°, γ = 90.00°, V =

poured into saturated aqueous NaCl (50 mL) and extracted 3522.7(9) Å³, Z = 8, T = 273.15 K, F000 = 1424.0, F000’ =

with CH₂Cl₂(3 × 20 mL). The combined organic phase 1425.78, R = 0.0621(2148), wR₂= 0.1579(3616). CCDC

was washed with water, dried over anhydrous MgSO₄, deposition number: 1858809. These data can be obtained

filtered, and evaporated in vacuo. The crude product was free of charge via www.ccdc.cam. ac.uk/conts/retrieving.

purified by column chromatography on silica gel with html (or from the Cambridge Crystallographic Data Center,

petroleum ether/ethyl acetate as the eluent to give the 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 (0)

corresponding product 3p-t.

1223 762911; or deposit @ccdc.cam.ac. uk).

4,4-Diethyl-1-(4-methoxyphenyl)-N,N-dimethyl-3,5-dio-

xopyrrolidine-2-carboxamide (3d): 272 mg, 82% yield;

Analytical data of 2a and 3

o

1

white solid; mp 178-179 C; H NMR (300 MHz, CDCl₃):

δ 7.38 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 5.36 (s,

1H), 3.80 (s, 3H), 3.26 (s, 3H), 2.96 (s, 3H), 1.81-1.89 (m,

4H), 0.92 (t, J = 7.5 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H); ¹³C

NMR (100 MHz, CDCl₃): δ 207.8, 174.1, 163.2, 158.0,

129.9, 125.5, 114.3, 68.7, 57.6, 55.4, 37.4, 36.4, 28.1, 9.2,

8.9; IR (KBr): 3075, 3049, 2973, 2940, 2928, 2883, 2839,

1762, 1680, 1660, 1609, 1591, 1518, 1496, 1460, 1431,

1414, 1401, 1303, 1251, 850 cm^-1. HRMS (ESI) m/z: [M +

Na]⁺Calcd for C₁₈H₂₄N₂O₄Na 355.1628, Found 355.1623.

2-[(Dimethylamino)methylene]-4,4-diethyl-5-(phenylim-

ino)dihydrofuran-3(2H)-one (2a): 183 mg, 64% yield;

1

pale yellow solid; Mp 37-38 ^oC; H NMR (300 MHz,

CDCl₃): δ 7.30 (t, J = 7.5 Hz, 2H), 7.04-7.10 (m, 3H), 6.61

(s, 1H), 2.98 (s, 6H), 1.75-1.97 (m, 4H), 0.92 (t, J = 7.5 Hz,

6H); ¹³C NMR (100 MHz, CDCl₃): δ 194.6, 161.0, 146.3,

128.5, 126.7, 126.4, 123.6, 122.4, 55.1, 30.6, 9.1; IR (KBr):

3066, 3044, 3011, 2962, 2919, 2876, 2844, 2813, 1693,

1625, 1619, 1594, 1487, 1458, 1436, 1423, 1381, 1361,

1346, 1284, 1250, 861, 770, 697 cm^-1. HRMS (ESI) m/z:

[M + Na]⁺Calcd for C₁₇H₂₂N₂O₂Na 309.1573, Found

309.1561.

1-(2,4-Dimethylphenyl)-4,4-diethyl-N,N-dimethyl-3,5-

dioxopyrrolidine-2-carboxamide (3e): 250 mg, 76% yield;

o

1

4,4-Diethyl-N,N-dimethyl-3,5-dioxo-1-phenylpyrrolidin-

e-2-carboxamide (3a): 245 mg, 81% yield; white solid;

mp 124-125 ^oC; ¹H NMR (400 MHz, CDCl₃): δ 7.49 (d, J =

white solid; mp 137-138 C; H NMR (300 MHz, CDCl₃):

δ 7.10-7.15 (m, 2H), 7.01 (d, J = 7.5 Hz, 1H), 5.35 (s, 1H),

3.14 (s, 3H), 2.91 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H), 1.82-

7.6 Hz, 2H), 7.39 (t, J = 7.2Hz, 2H), 7.22 (t, J = 7.2 Hz, 1.92 (m, 4H), 0.95 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz,

1H), 5.45 (s, 1H), 3.31 (s, 3H), 2.97 (s, 3H), 1.82-1.91 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 208.2, 173.8, 163.5,

4H), 0.93 (t, J = 7.6 Hz, 3H), 0.89 (t, J = 7.6 Hz, 3H); ¹³C

138.0, 136.3, 132.6, 132.0, 127.2, 68.9, 57.2, 37.4, 36.4,

NMR (100 MHz, CDCl₃): δ 207.4, 174.1, 163.0, 137.1,

129.1, 126.2, 122.9, 68.2, 58.0, 37.4, 36.5, 28.1, 9.2, 8.9;

IR (KBr): 3057, 3044, 2970, 2938, 2882, 2856, 1762, 1682,

28.1, 27.8, 21.0, 18.5, 9.3, 9.0; IR (KBr): 2973, 2940, 2930,

2883, 2867, 1762, 1682, 1658, 1615, 1582, 1508, 1460,

1436, 1419, 1391, 1307, 1256, 861, 811 cm^-1. HRMS (ESI)

1664, 1597, 1500, 1460, 1435, 1401, 1389, 1344, 1300, m/z: [M + Na]⁺Calcd for C₁₉H₂₆N₂O₃Na 353.1836, Found

1257, 758, 698. HRMS (ESI) m/z: [M + Na]⁺Calcd for 353.1819.

C₁₇H₂₂N₂O₃Na 325.1523, Found 325.1512.

4,4-Diethyl-N,N-dimethyl-3,5-dioxo-1-(o-tolyl)pyrrolid-

4,4-Diethyl-N,N-dimethyl-3,5-dioxo-1-(p-tolyl)pyrrolidi-

ne-2-carboxamide (3b): 249 mg, 79% yield; white solid;

ine-2-carboxamide (3f): 214 mg, 68% yield; white solid;

o

1

mp 151-153 C; H NMR (300 MHz, CDCl₃): δ 7.19-7.30

mp 159-161 ^oC; ¹H NMR (300 MHz, CDCl₃): δ 7.36 (d, J = (m, 4H), 5.38 (s, 1H), 3.15 (s, 3H), 2.91 (s, 3H), 2.42 (s,

8.4 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 5.41 (s, 1H), 3.29 (s, 3H), 1.84-1.93 (m, 4H), 0.97 (t, J = 7.2 Hz, 3H), 0.94 (t, J

= 7.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 208.1,

3H), 2.96 (s, 3H), 2.33 (s, 3H), 1.81-1.89 (m, 4H), 0.92 (t, J

= 7.5 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H); ¹³C NMR (100

173.7, 163.4, 136.9, 135.3, 131.4, 128.2, 126.5, 68.9, 57.3,

6

10.1002/adsc.201801237

Advanced Synthesis & Catalysis

37.5, 36.4, 28.2, 27.9, 18.6, 9.4, 9.0; IR (KBr): 3052, 3029, J = 8.1 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.18 (t, J = 7.5 Hz,

2973, 2942, 2883, 2861, 1761, 1686, 1658, 1604, 1583, 1H), 6.22 (s, 1H), 3.27 (s, 3H), 2.84 (s, 3H), 1.91-2.01 (m,

1497, 1459, 1437, 1420, 1404, 1388, 1307, 1258, 761 cm^-1. 3H), 1.68-1.85 (m, 5H); ¹³C NMR (100 MHz, CDCl₃): δ

HRMS (ESI) m/z: [M + Na]⁺Calcd for C₁₈H₂₄N₂O₃Na 207.5, 175.7, 163.7, 137.2, 129.1, 125.9, 122.4, 67.3, 57.7,

339.1679, Found 339.1665.

38.4, 37.4, 36.5, 34.5, 27.0, 26.9; IR (KBr): 3059, 3040,

2961, 2942, 2870, 1762, 1686, 1664, 1595, 1493, 1455,

1415, 1400, 1293, 1254, 752, 698 cm^-1. HRMS (ESI) m/z:

[M + Na]⁺Calcd for C₁₇H₂₀N₂O₃Na 323.1366, Found

323.1353.

4,4-Diethyl-1-(2-methoxyphenyl)-N,N-dimethyl-3,5-dio-

xopyrrolidine-2-carboxamide (3g): 235 mg, 71% yield;

o

1

white solid; mp 145-146 C; H NMR (300 MHz, CDCl₃):

δ 7.62 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.03 (t,

J = 7.5 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 5.54 (s, 1H), 3.83

N,N-Dimethyl-1,4-dioxo-2-(p-tolyl)-2-azaspiro[4.4]nona-

(s, 3H), 3.16 (s, 3H), 2.90 (s, 3H), 1.78-1.90 (m, 4H), 0.94 ne-3-carboxamide (3l): 254 mg, 81% yield; white solid;

(t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 mp 185-186 ^oC; ¹H NMR (300 MHz, CDCl₃): δ 7.36 (d, J =

MHz, CDCl₃): δ 209.0, 174.8, 163.4, 154.2, 131.8, 129.2, 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 5.50 (s, 1H), 3.28 (s,

124.2, 121.0, 111.4, 67.9, 56.8, 55.5, 37.3, 36.2, 28.3, 28.2, 3H), 2.97 (s, 3H), 2.32 (s, 3H), 2.21-2.32 (m, 1H), 2.05-

9.1, 9.0; IR (KBr): 3082, 3021, 2972, 2966, 2937, 2880, 2.13 (m, 1H), 1.79-2.00 (m, 6H); ¹³C NMR (100 MHz,

2847, 1762, 1706, 1657, 1621, 1598, 1501, 1459, 1442, CDCl₃): δ 207.7, 175.6, 163.8, 135.8, 134.6, 129.7, 122.6,

1401, 1381, 1267, 758 cm^-1. HRMS (ESI) m/z: [M + Na]⁺67.5, 57.6, 38.4, 37.4, 36.5, 34.4, 27.0, 26.9, 20.9; IR

Calcd for C₁₈H₂₄N₂O₄Na 355.1628, Found 355.1612.

(KBr): 3061, 3034, 2952, 2869, 1764, 1697, 1647, 1613,

1517, 1446, 1422, 1409, 1388, 1299, 1259, 815 cm^-1.

HRMS (ESI) m/z: [M + Na]⁺Calcd for C₁₈H₂₂N₂O₃Na

337.1523, Found 337.1513.

1-(3-Chlorophenyl)-4,4-diethyl-N,N-dimethyl-3,5-dioxo-

pyrrolidine-2-carboxamide (3h): 252 mg, 75% yield;

o

1

white solid; mp 112-113 C; H NMR (300 MHz, CDCl₃):

δ 7.59 (s, 1H), 7.28-7.36 (m, 2H), 7.20 (dt, J₁= 6.9 Hz, J₂=

2-(2,4-Dimethylphenyl)-N,N-dimethyl-1,4-dioxo-2-azas-

1.8 Hz, 1H), 5.43 (s, 1H), 3.34 (s, 3H), 2.99 (s, 3H), 1.81- piro[4.4]nonane-3-carboxamide (3m): 259 mg, 79%

o

1

1.89 (m, 4H), 0.91 (t, J = 7.5 Hz, 3H), 0.88 (t, J = 7.5 Hz, yield; white solid; mp 172-173 C; H NMR (300 MHz,

3H); ¹³C NMR (100 MHz, CDCl₃): δ 206.7, 174.1, 162.6, CDCl₃): δ 7.19 (d, J = 7.5 Hz, 1H), 7.09 (s, 1H), 7.01 (d, J

138.3, 134.7, 130.0, 126.2, 122.8, 120.6, 67.9, 58.1, 37.5, = 8.1 Hz, 1H), 5.34 (s, 1H), 3.10 (s, 3H), 2.92 (s, 3H), 2.31

36.5, 28.1, 28.1, 9.2, 8.9; IR (KBr): 3068, 3044, 2985, 2971, (s, 3H), 2.29 (s, 3H), 2.21-2.29 (m, 1H), 1.76-2.13 (m, 7H);

2945, 2927, 2883, 2863, 1765, 1703, 1650, 1593, 1481, ¹³C NMR (100 MHz, CDCl₃): δ 208.5, 175.4, 164.4, 138.1,

1450, 1447, 1433, 1406, 1390, 1336, 1257, 878, 788, 749, 135.9, 132.5, 131.9, 127.3, 126.7, 68.1, 56.7, 38.2, 37.4,

705 cm^-1. HRMS (ESI) m/z: [M + Na]⁺Calcd for 36.4, 34.1, 27.0, 26.8, 21.0, 18.0; IR (KBr): 3028, 3014,

C₁₇H₂₁ClN₂O₃Na 359.1133, Found 359.1120.

2999, 2955, 2936, 2866, 1761, 1704, 1654, 1609, 1497,

1457, 1447, 1405, 1390, 1295, 1255, 822, 768 cm^-1. HRMS

(ESI) m/z: [M + Na]⁺Calcd for C₁₉H₂₄N₂O₃Na 351.1679,

Found 351.1667.

1-Benzyl-4,4-diethyl-N,N-dimethyl-3,5-dioxopyrrolidine

-2-carboxamide (3i): 221 mg, 70% yield; white solid; mp

o

1

105-106 C; H NMR (300 MHz, CDCl₃): δ 7.32-7.34 (m,

3H), 7.21 (d, J = 6.3 Hz, 2H), 5.55 (d, J = 14.4 Hz, 1H),

2-(2-Methoxyphenyl)-N,N-dimethyl-1,4-dioxo-2-azaspi-

4.49 (s, 1H), 3.91 (d, J = 14.4 Hz, 1H), 3.01 (s, 3H), 2.94 (s, ro[4.4]nonane-3-carboxamide (3n): 244 mg, 74% yield;

o

1

3H), 1.69-1.88 (m, 4H), 0.84 (t, J = 7.5 Hz, 3H), 0.77 (t, J white solid; mp 132-134 C; H NMR (300 MHz, CDCl₃):

= 7.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 208.1, δ 7.61 (dd, J₁= 7.8 Hz, J₂= 1.5 Hz, 1H), 7.29 (td, J₁= 8.1

174.3, 162.8, 135.2, 128.9, 128.1, 65.1, 57.2, 44.5, 37.1, Hz, J₂= 1.5 Hz, 1H), 7.02 (td, J₁= 7.5 Hz, J₂= 0.9 Hz, 1H),

36.3, 28.1, 27.9, 9.2, 9.0; IR (KBr): 3063, 3030, 2971, 2939, 6.94 (d, J = 8.4 Hz, 1H), 5.66 (s, 1H), 3.84 (s, 3H), 3.14 (s,

2883, 1762, 1694, 1682, 1652, 1587, 1496, 1453, 1425, 3H), 2.90 (s, 3H), 2.21-2.30 (m, 1H), 2.04-2.14 (m, 1H),

1416, 1388, 1349, 1308, 1259, 761, 701 cm^-1. HRMS (ESI) 1.78-2.00 (m, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 208.9,

m/z: [M + Na]⁺Calcd for C₁₈H₂₄N₂O₃Na 339.1679, Found 176.5, 164.3, 154.1, 131.2, 129.0, 124.3, 121.1, 111.5, 67.0,

339.1666.

56.3, 55.6, 37.8, 37.2, 36.3, 34.6, 27.0, 26.9; IR (KBr):

3088, 3066, 3020, 2960, 2953, 2928, 2869, 2833, 1764,

1703, 1657, 1598, 1502, 1461, 1437, 1413, 1401, 1386,

1301, 1267, 752 cm^-1. HRMS (ESI) m/z: [M + Na]⁺Calcd

for C₁₈H₂₂N₂O₄Na 353.1472, Found 353.1452.

4,4-Dibutyl-N,N-dimethyl-3,5-dioxo-1-phenylpyrrolidi-

ne-2-carboxamide (3j): 272 mg, 76% yield; white solid;

mp 140-142 ^oC; ¹H NMR (300 MHz, CDCl₃): δ 7.48 (d, J =

7.5 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.22 (t, J = 7.5 Hz,

1H), 5.46 (s, 1H), 3.31 (s, 3H), 2.97 (s, 3H), 1.73-1.89 (m,

N,N,2-Trimethyl-1,4-dioxo-2-azaspiro[4.4]nonane-3-ca-

4H), 1.07-1.39 (m, 8H), 0.86 (t, J = 7.2 Hz, 3H), 0.85 (t, J rboxamide (3o): 147 mg, 62% yield; white solid; mp 140-

= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 207.6, 141 C; H NMR (300 MHz, CDCl₃): δ 4.95 (s, 1H), 3.26

174.3, 162.9, 137.2, 129.1, 126.2, 122.9, 68.1, 57.0, 37.5, (s, 3H), 3.02 (s, 3H), 2.95 (s, 3H), 1.94-2.09 (m, 2H), 1.73-

36.5, 35.3, 35.1, 26.9, 26.1, 22.9, 13.7, 13.6; IR (KBr): 1.91 (m, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 208.1, 176.2,

3064, 3042, 2961, 2933, 2874, 2862, 1765, 1703, 1652, 163.4, 67.7, 56.1, 37.4, 37.3, 36.4, 34.0, 28.3, 26.8, 26.7;

1598, 1498, 1457, 1438, 1405, 1385, 1299, 1254, 755, 694 IR (KBr): 2963, 2947, 2874, 1763, 1686, 1651, 1483, 1452,

o

1

cm^-1. HRMS (ESI) m/z: [M

C₂₁H₃₀N₂O₃Na 381.2149, Found 381.2139.

+

Na]⁺Calcd for 1435, 1393, 1311, 1289, 1254 cm^-1. HRMS (ESI) m/z: [M

+ Na]⁺Calcd for C₁₂H₁₈N₂O₃Na 261.1210, Found 261.1207.

N,N-Dimethyl-1,4-dioxo-2-phenyl-2-azaspiro[4.4]nona-

N,N-Dimethyl-4,7-dioxo-5-phenyl-5-azaspiro[2.4]hepta-

ne-3-carboxamide (3k): 252 mg, 84% yield; white solid; ne-6-carboxamide (3p): 176 mg, 65% yield; white solid;

mp 133-135 ^oC; ¹H NMR (300 MHz, DMSO-d₆): δ 7.53 (d, mp 159-160 ^oC; ¹H NMR (300 MHz, CDCl₃): δ 7.50 (d, J =

7

10.1002/adsc.201801237

Advanced Synthesis & Catalysis

7.8 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.20 (t, J = 7.2 Hz, 692 cm^-1. HRMS (ESI) m/z: [M + Na]⁺Calcd for

1H), 5.68 (s, 1H), 3.32 (s, 3H), 2.99 (s, 3H), 1.82-1.95 (m, C₁₈H₂₂N₂O₃Na 337.1523, Found 337.1511.

2H), 1.68-1.79 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ

202.2, 171.3, 163.5, 137.4, 129.1, 125.7, 121.9, 67.6, 37.4,

36.5, 32.2, 23.4, 21.4; IR (KBr): 3111, 3079, 3061, 2967,

Acknowledgements

1755, 1709, 1651, 1596, 1495, 1458, 1439, 1404, 1383,

1348, 1300, 1254, 1028, 761, 694 cm^-1. HRMS (ESI) m/z:

[M + Na]⁺Calcd for C₁₅H₁₆N₂O₃Na 295.1053, Found

295.1045.

A Financial support of this research by the National Natural

Science Foundation of China (21502185 and 21542006) and the

Department of Science and Technology of Jilin Province

(20170203005SF) is greatly acknowledged. C. B. Rao thanks the

award of CAS President's International Fellowship for

Postdoctoral Researchers (2016PT021), and R. Zhang thanks

the support of Youth Innovation Promotion Association

CAS (2018261).

N,N-Dimethyl-4,7-dioxo-5-(p-tolyl)-5-azaspiro[2.4]hept-

ane-6-carboxamide (3q): 197 mg, 69% yield; white solid;

mp 193-194 ^oC; ¹H NMR (300 MHz, CDCl₃): δ 7.38 (d, J =

8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.65 (s, 1H), 3.29 (s,

3H), 2.98 (s, 3H), 2.33 (s, 3H), 1.80-1.93 (m, 2H), 1.67-

1.77 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 202.4, 171.2,

163.6, 135.6, 134.8, 129.7, 122.2, 67.8, 37.4, 36.5, 32.2,

2.3.2, 21.3, 20.9; IR (KBr): 3034, 2969, 2935, 2869, 1755,

1707, 1651, 1515, 1436, 1423, 1406, 1386, 1348, 1301,

1255, 1019, 823 cm^-1. HRMS (ESI) m/z: [M + Na]⁺Calcd

for C₁₆H₁₈N₂O₃Na 309.1210, Found 309.1200.

References

[1] For reviews, see: a) H.-G. Henning, A. Gelbin, Adv.

Heterocycl. Chem. 1993, 57, 139-185; b) B. J. L.

Royles, Chem. Rev. 1995, 95, 1981-2001; c) R.

Schobert, A. Schlenk, Bioorg. Med. Chem. 2008, 16,

4203-4221; d) P.-Q. Huang, Synlett 2006, 1133-1149;

e) A. S. Ivanov, Chem. Soc. Rev. 2008, 37, 789-811; f)

D. Boettger, C. Hertweck, ChemBioChem 2013, 14,

28-42.

[2] a) T. B. Kakule, S. Zhang, J. Zhan, E. W. Schmidt,

Org. Lett. 2015, 17, 2295-2297; b) R. G. Haase, R.

Schobert, Org. Lett. 2016, 18, 6352-6355; c) C. M.

Haskins, D. W. Knight, Chem. Commun. 2005, 3162-

3164; d) T. Wakimoto, T. Mori, H. Morita, I. Abe, J.

Am. Chem. Soc. 2011, 133, 4746-4749; e) X. Li, Q.

Zheng, J. Yin, W. Liu, S. Gao, Chem. Commun. 2017,

53, 4695-4697; f) J. Li, S. Liu, S. Niu, W. Zhuang, Y.

Che, J. Nat. Prod. 2009, 72, 2184-2187.

[3] a) E. J. Corey, W. Li, T. Nagamitsu, Angew. Chem.

Int. Ed. 1998, 37, 1676-1679; Angew. Chem. 1998,

110, 1784-1787; b) H. H. Dhanjee, Y. Kobayashi, J. F.

Buergler, T. C. McMahon, M. W. Haley, J. M.

Howell, K. Fujiwara, J. L. Wood, J. Am. Chem. Soc.

2017, 139, 14901-14904; c) X.-B. Li, L. Li, R.-X. Zhu,

W. Li, W.-Q. Chang, L.-L. Zhang, X.-N. Wang, Z.-T.

Zhao, H.-X. Lou, J. Nat. Prod. 2015, 78, 2155-2160;

d) J. C. Carlson, S. Li, D. A. Burr, D. H. Sherman, J.

Nat. Prod. 2009, 72, 2076-2079; e) J. Y. Li, G.

Strobel, J. Harper, E. Lobkovsky, J. Clardy, Org. Lett.

2000, 2, 767-770.

[4] a) X. Cheng, F. Liang, F. Shi, L. Zhang, Q. Liu, Org.

Lett. 2009, 11, 93-96; b) A. Padwa, J. P. Snyder, E. A.

Curtis, S. M. Sheehan, K. J. Worsencroft, C. O.

Kappe, J. Am. Chem. Soc. 2000, 122, 8155-8167; c) R.

A. Shenvi, E. J. Corey, J. Am. Chem. Soc. 2009, 131,

5746-5747; d) J. J. Leban, K. L. Colson, J. Org.

Chem. 1996, 61, 228-231; e) S. Fustero, M. García de

la Torre, J. F. Sanz-Cervera, C. Ramírez de Arellano,

J. Piera, A. Simón, Org. Lett. 2002, 4, 3651-3654; f)

C.-P. Xu, P.-Q. Huang, S. Py, Org. Lett. 2012, 14,

2034-2037.

4,4-Diallyl-N,N-dimethyl-3,5-dioxo-1-phenylpyrrolidine

-2-carboxamide (3r): 234 mg, 72% yield; white solid; mp

o

1

146-147 C; H NMR (300 MHz, CDCl₃): δ 7.43-7.47 (m,

2H), 7.38 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 5.62-

5.88 (m, 2H), 5.35 (s, 1H), 5.08-5.18 (m, 4H), 3.27 (s, 3H),

2.96 (s, 3H), 2.45-2.63 (m, 4H); ¹³C NMR (100 MHz,

CDCl₃): δ 205.4, 172.9, 163.0, 137.0, 131.4, 131.2, 129.1,

126.4, 123.1, 120.2, 119.4, 68.2, 56.8, 38.9, 38.4, 37.4,

36.5; IR (KBr): 3076, 3044, 3004, 2979, 2940, 2913, 2835,

1769, 1699, 1654, 1598, 1500, 1458, 1431, 1418, 1406,

1374, 1252, 996, 920, 766, 693 cm^-1. HRMS (ESI) m/z: [M

+ Na]⁺Calcd for C₁₉H₂₂N₂O₃Na 349.1523, Found 349.1511.

4,4-Diallyl-1-(4-chlorophenyl)-N,N-dimethyl-3,5-dioxo-

pyrrolidine-2-carboxamide (3s): 216 mg, 60% yield;

o

1

white solid; mp 89-91 C; H NMR (300 MHz, CDCl₃): δ

7.40 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 9.0 Hz, 2H), 5.60-

5.84 (m, 2H), 5.31 (s, 1H), 5.07-5.18 (m, 4H), 3.28 (s, 3H),

2.96 (s, 3H), 2.45-2.62 (m, 4H); ¹³C NMR (100 MHz,

CDCl₃): δ 204.9, 172.9, 162.6, 135.5, 131.8, 131.2, 131.0,

129.2, 124.4, 120.4, 119.6, 68.2, 56.8, 39.0, 38.5, 37.5,

36.5; IR (KBr): 3090, 3054, 3038, 2983, 2935, 2868, 1769,

1685, 1663, 1643, 1594, 1498, 1445, 1418, 1401, 1386,

1256, 993, 924, 829 cm^-1. HRMS (ESI) m/z: [M + Na]⁺

Calcd for C₁₉H₂₁ClN₂O₃Na 383.1133, Found 383.1121.

4-Allyl-4-ethyl-N,N-dimethyl-3,5-dioxo-1-phenylpyrrol-

idine-2-carboxamide (3t): 232 mg, 74% yield, 1.3:1 dr;

white solid; ¹H NMR (300 MHz, CDCl₃): δ 7.47 (t, J = 7.5

Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 6.9 Hz, 1H),

5.64-5.87 (m, 1H), 5.45 (s, 0.4H, dia.2), 5.35 (s, 0.6H,

dia.1), 5.06-5.18 (m, 2H), 3.30 (s, 1.3H, dia.2), 3.28 (s,

1.7H, dia.1), 2.96 (s, 3H), 2.43-2.63 (m, 2H), 1.84-1.89 (m,

2H), 0.94 (t, J = 7.5 Hz, 1.7H, dia.1), 0.88 (t, J = 7.2 Hz,

1.3H, dia.2); ¹³C NMR (100 MHz, CDCl₃): δ 206.7 &

206.1 (dia.1/dia.2), 173.5, 162.9, 137.0, 131.5, 129.1, 126.3,

123.2 & 122.9 (dia.1/dia.2), 120.1 & 119.1 (dia.1/dia.2),

68.2, 57.8 & 57.3 (dia.1/dia.2), 39.2, 37.4, 36.5, 28.0 &

27.4 (dia.1/dia.2), 8.9 & 9.1 (dia.1/dia.2); IR (KBr): 3076,

3067, 3043, 2969, 2938, 2880, 1765, 1699, 1652, 1598,

1496, 1458, 1434, 1406, 1382, 1297, 1254, 996, 923, 760,

[5] a) M. Hosseini, H. Kringelum, A. Murray, J. E.

Tønder, Org. Lett. 2006, 8, 2103-2106; b) T.

Wakimoto, T. Mori, H. Morita, I. Abe, J. Am. Chem.

Soc. 2011, 133, 4746-4749; c) Y.-C. Jeong, M. G.

8

10.1002/adsc.201801237

Advanced Synthesis & Catalysis

Moloney, J. Org. Chem. 2011, 76, 1342-1354; d) K.

Yang, D. Dong, Org. Lett. 2007, 9, 5345-5348; i) L.

Mao, Y. Li, T. Xiong, K. Sun, Q. Zhang, J. Org.

Chem. 2013, 78, 733-737; j) S. Maiti, T. K. Achar, P.

Mal, Org. Lett. 2017, 19, 2006-2009.

Aikawa, M. Asano, K. Ono, N. Habuka, J. Yano, K.

Wilson, H. Fujita, H. Kandori, T. Hara, M. Morimoto,

T. Santou, M. Yamaoka, M. Nakayama, A. Hasuoka,

Bioorg. Med. Chem. 2017, 25, 3330-3349.

[14] J. Huang, Y. Liang, W. Pan, Y. Yang, D. Dong, Org.

Lett. 2007, 9, 5345-5348.

[6] a) B. A. Kulkarni, A. Ganesan, Angew. Chem. Int. Ed.

1997, 36, 2454-2455; Angew. Chem. 1997, 109, 2565- [15] P. Huang, X. Fu, Y. Liang, R. Zhang, D. Dong, Aust.

2567; b) J. W. Sims, E. W. Schmidt, J. Am. Chem. J. Chem. 2012, 65, 121-128.

Soc. 2008, 130, 11149-11155; c) P. C. Bulman Page, [16] J. Huang, Y. Lu, B. Qiu, Y. Liang, N. Li, D. Dong,

A. S. Hamzah, D. C. Leach, S. M. Allin, D. M. Synthesis 2007, 2791-2796.

Andrews, G. A. Rassias, Org. Lett. 2003, 5, 353-355; [17] K. Wang, X. Fu, J. Liu, Y. Liang, D. Dong, Org. Lett.

d) R. Yendapally, J. G. Hurdle, E. I. Carson, R. B. 2009, 11, 1015-1018.

Lee, R. E. Lee, J. Med. Chem. 2008, 51, 1487-1491; [18] J. Yuan, C. B. Rao, Q. Zhang, R. Zhang, Y. Liang, N.

e) N. A. Butt, C. J. Moody, Org. Lett. 2011, 13, 2224-

2227.

[7] A. Miyadera, K. Satoh, A. Imura, Chem. Pharm. Bull.

2000, 48, 563-565.

[8] a) A. P. Michael, E. J. Grace, M. Kotiw, R. A. Barrow,

J. Nat. Prod. 2002, 65, 1360-1362; b) T. Sengoku, Y.

Nagae, Y. Ujihara, M. Takahashi, H. Yoda, J. Org.

Chem. 2012, 77, 4391-4401; c) K. Kempf, A. Raja, F.

Sasse, R. Schobert, J. Org. Chem. 2013, 78, 2455-

2461.

[9] a) B. Alcaide, P. Almendros, A. Luna, S. Cembellín,

M. Arnó, L. R. Domingo, Chem. Eur. J. 2011, 17,

11559-11566; b) B. Alcaide, P. Almendros, A. Luna,

Zhang, D. Dong, Synthesis 2018, 50, 1875-1882.

[19] X. Liu, X. Xin, D. Xiang, Y. Liang, X. Xin, W. Li, D.

Dong, RSC Adv. 2013, 3, 1346-1349.

[20] a) Y. Yamane, K. Miyazaki, T. Nishikata, ACS Catal.

2016, 6, 7418-7425. b) A. Correa, I. Tellitu, E.

Dominguez, R. SanMartin, J. Org. Chem. 2006, 71,

3501-3505; c) D. Anand, O. P. S. Patel, R. K. Maurya,

R. Kant, P. P. Yadav, J. Org. Chem. 2015, 80, 12410-

12419; d) A. Padwa, J. P. Snyder, E. A. Curtis, S. M.

Sheehan, K. J. Worsencroft, C. O. Kappe, J. Am.

Chem. Soc. 2000, 122, 8155-8167; e) U. Farid, T.

Wirth, Angew. Chem. Int. Ed. 2012, 51, 3462 –3465;

Angew. Chem. 2012, 124, 3518-3522.

M. R. Torres, Adv. Synth. Catal. 2010, 352, 621-626; [21] J. Yuan, Q. Zhang, M. Yu, P. Huang, R. Zhang, D.

c) B. Alcaide, Y. Martín-Cantalejo, J. Rodríguez- Dong, Org. Lett. 2015, 17, 5012-5015.

López, M. A. Sierra, J. Org. Chem. 1993, 58, 4767- [22] a) R. Zhang, Y. Liang, G. Zhou, K. Wang, D. Dong, J.

4770.

Org. Chem. 2008, 73, 8089-8092; b) P. Huang, N.

Zhang, R. Zhang, D. Dong, Org. Lett. 2012, 14, 370-

373.

[10] a) D. Farran, I. Parrot, J. Martinez, G. Dewynter,

Angew. Chem. Int. Ed. 2007, 46, 7488-7490; Angew.

Chem. 2007, 119, 7632-7634; b) G. Chaubet, T. [23] J. Sun, D. Zhang-Negrerie, Y. Du, K. Zhao, J. Org.

Coursindel, X. Morelli, S. Betzi, P. Roche, Y. Guari, Chem. 2015, 80, 1200-1206.

A. Lebrun, L. Toupet, Y. Collette, I. Parrot, J. [24] C.-Y. Liu, Y. Li, J.-Y. Ding, D.-W Dong, F.-S. Han,

Martinez, Org. Biomol. Chem. 2013, 11, 4719-4726. Chem. Eur. J. 2014, 20, 2373-2381.

[11] a) X. Bi, J. Zhang, Q. Liu, J. Tan, B. Li, Adv. Synth. [25] a) L. M. Huffman, S. S. Stahl, J. Am. Chem. Soc.

Catal. 2007, 349, 2301-2306; b) Y. Li, X. Xu, J. Tan,

P. Liao, J. Zhang, Q. Liu, Org. Lett. 2010, 12, 244-

247.

2008, 130, 9196-9197; b) A. Casitas, A. E. King, T.

Parella, M. Costas, S. S. Stahl, X. Ribas, Chem. Sci.

2010, 1, 326–330; c) D. E. Mancheno, A. R. Thornton,

A. H. Stoll, A. Kong, S. B. Blakey, Org. Lett. 2010,

12, 4110-4113; d) S. Sanjaya, S. Chiba, Org. Lett.

2012, 14, 5342-5345.

[12] For reviews, see: a) V. V. Zhdankin, P. J. Stang,

Chem. Rev. 2002, 102, 2523-2584; b) P. J. Stang, J.

Org. Chem. 2003, 68, 2997-3008; c) H. Tohma, Y.

Kita, Adv. Synth. Catal. 2004, 346, 111-124; d) F. [26] a) H. Hamamoto, Y. Shiozaki, H. Nambu, K. Hata, H.

Collet, C. Lescot, P. Dauban, Chem. Soc. Rev. 2011,

40, 1926-1936; e) M. L. Louillat, F. W. Patureau,

Chem. Soc. Rev. 2014, 43, 901-910; f) L. F. Silva Jr.,

B. Olofsson, Nat. Prod. Rep. 2011, 28, 1722-1754; g)

A. Yoshimura, V. V. Zhdankin, Chem. Rev. 2016, 116,

3328-3435.

Tohma, Y. Kita, Chem. Eur. J. 2004, 10, 4977-4982;

b) T. Dohi, K. Morimoto, Y. Kiyono, H. Tohma, Y.

Kita, Org. Lett. 2005, 7, 537-540; c) T. Takada, M.

Arisawa, M. Gyoten, R. Hamada, H. Tohma, Y. Kita,

J. Org. Chem. 1998, 63, 7698-7706; d) T. Dohi, K.

Morimoto, A. Maruyama, Y. Kita, Org. Lett. 2006, 8,

2007-2010.

[13] a) Y. Kikugawa, M. Kawase, Chem. Lett. 1990, 581-

582; b) D. J. Wardrop, W. Zhang, Org. Lett. 2001, 3, [27] a) Y. Du, R. Liu, G. Linn, K. Zhao, Org. Lett. 2006, 8,

2353-2356; c) N. Itoh, T. Sakamoto, E. Miyazawa, Y.

Kikugawa, J. Org. Chem. 2002, 67, 7424-7428; d) Y.

Kikugawa, A. Nagashima, T. Sakamoto, E. Miyazawa,

M. Shiiya, J. Org. Chem. 2003, 68, 6739-6744; e) S.

Serna, I. Tellitu, E. Dominguez, I. Moreno, R.

5919-5922; b) J. Huang, Y. He, Y. Wang, Q. Zhu,

Chem. Eur. J. 2012, 18, 13964-13967; c) R. Narayana,

S. Mannaa, A. P. Antonchick, Synlett 2015, 26, 1785-

1803; d) J.-R. Chen, X.-Y. Yu, W.-J. Xiao, Synthesis

2015, 47, 604-629.

SanMartin, Org. Lett. 2005, 7, 3073-3076; f) A. [28] F. Wang, W. Sun, Y. Wang, Y. Jiang, T.-P. Loh, Org.

Correa, I. Tellitu, E. Dominguez, R. SanMartin, J. Lett. 2018, 20, 1256-1260.

Org. Chem. 2006, 71, 8316-8319; g) A Correa, I. [29] J. Clarke, K. J. Bonney, M. Yaqoob, S. Solanki, H. S.

Tellitu, E. Dominguez, R. SanMartin, Org. Lett. 2006,

8, 4811-4813; h) J. Huang, Y. Liang, W. Pan, Y.

Rzepa, A. J. P. White, D. S. Millan, D. C. Braddock. J.

Org. Chem. 2016, 81, 9539-9552.

9

10.1002/adsc.201801237

Advanced Synthesis & Catalysis

[30] a) Y. Kita, Y. Nishii, T. Higuchi, K. Mashima. Angew.

Chem. Int. Ed. 2012, 51, 5723-5726. Angew. Chem.

2012, 124, 5821-5824; b) C. C. D. Wybon, C. Mensch,

K. Hollanders, C. Gadais, ̀ W. A. Herrebout, S. Ballet,

B. U. W. Maes. ACS Catal. 2018, 8, 203-218; c) E. S.

Elton, T. Zhang, R. Prabhakar, A. M. Arif, L. M.

Berreau. Inorg. Chem. 2013, 52, 11480-11492.

[31] a) J. Yu, J. Tian, C. Zhang, Adv. Synth. Catal. 2010,

352, 531-546; b) Y. Sun, R. Fan, Chem. Commun.

2010, 46, 6834-6836.

[32] B. L. Tran, B. Li, M. Driess, J. F. Hartwig, J. Am.

Chem. Soc. 2014, 136, 2555-2563.

10

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Advanced Synthesis & Catalysis

Copper-Catalyzed Regioselective Oxidative Cycloamidation

FULL PAPER

Copper-Catalyzed Regioselective Oxidative Cyclo-

amidation of α-[(β-Dimethylamino)propenoyl]-

Alkylamides: Synthetic Route to Substituted

Pyrrolidine-2,4-diones

Adv. Synth. Catal. Year, Volume, Page – Page

Jingwen Yuan, Chitturi Bhujanga Rao, Yongjiu

Liang, Rui Zhang,* Qian Zhang, Liman Hou, and

Dewen Dong*

11

Article Doi

Copper-Catalyzed Regioselective Oxidative Cycloamidation of α-[(β-Dimethylamino)propenoyl]-Alkylamides: Synthetic Route to Substituted Pyrrolidine-2,4-diones

DOI: 10.1002/adsc.201801237

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