Stereospecific Synthesis of Highly Substituted Piperazines via an One

Subscriber access provided by Université de Strasbourg - Service Commun de la Documentation

Article

Stereospecific Synthesis of Highly Substituted Piperazines via a One-Pot Three Component Ring-Opening Cyclization from N-activated Aziridines, Anilines and Propargyl Carbonates Navya Chauhan, Sajan Pradhan, and Manas K. Ghorai J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02259 • Publication Date (Web): 26 Oct 2018 Downloaded from http://pubs.acs.org on October 26, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Stereospecific Synthesis of Highly Substituted Piperazines via a One-Pot Three Component Ring-Opening Cyclization from N-activated Aziridines, Anilines and Propargyl Carbonates Navya Chauhan, Sajan Pradhan and Manas K Ghorai* Department of Chemistry, Indian Institute of Technology, Kanpur, 208016, India Fax: (+91)-512-2596806; Phone: (+91)-512-2597518; email: [email protected] SO2Ar1 N + Ar3NH2 Ar2

1

2

i) rt, 1.5 h ii)

OBoc

N

R Ar1O2S

N

Ar3 Ar2

4 3 R up to 91% yield, ee >99% Pd(PPh3)4 (0.1 equiv) (17 examples) ()-BINAP (0.2 equiv) DMSO, 120 °C, 5-30 min

 wide substrate scope  stereospecific  mild conditions

Abstract: A simple and efficient one-pot three-component synthetic route to highly substituted and functionalizable piperazines in high yields with excellent stereoselectivity (de, ee >99%) is reported. The SN2-type ring-opening of N-activated aziridines by anilines followed by Pdcatalyzed annulation with propargyl carbonates gives rise to the final piperazine products. Introduction Piperazines are an important class of heterocyclic compounds exhibiting significant biological and pharmacological activities and are of special interest and applicability in the drug industry.1 Various piperazine derivatives are known to show anti-viral,2 anti-depressant,3 anti-tumor,4

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 32

anxiolytic5 and antimicrobial6 activities (Figure 1). Furthermore, piperazine derivatives are used in asymmetric catalysis7 as well as organocatalysis8 and also as ligands in various metal-catalyzed reactions.9 A number of strategies have been developed for their syntheses. Some recent reports include a biocatalytic approach from 1,2-dicarbonyl and 1,2-diamine substrates,10a from aldehydes and SnAP reagents using continuous flow photo-chemistry10b and from amino acids.10c In another report, 5-oxopiperazine-2-carboxamides and carboxylic acids were converted into cis- and transconfigured bicyclic piperazines.10d Other strategies include synthesis of piperazine derivatives from optically active acids using a resolution technique10e and a palladium-catalyzed decarboxylative cyclization of propargyl carbonates with bis-nitrogen nucleophiles for the syntheses of highly substituted piperazine compounds (Scheme 1).10 Though there are numerous reports for syntheses of N-substituted piperazines, there are only a few reports for efficient syntheses of carbon-substituted piperazines with high regio- and enantioselectivity. Figure 1. Some important compounds having piperazine cores

O

H N

H N

N

N HN

O

OH

S

N

OH Indinavir (anti-HIV)

Vortioxetine (anxiolytic)

N

O

N N

N

NH OH

F

S

HN

N

N

N O

O Ph HO O Seroquel XR Pefloxacin (S)-3-benzylpiperazine-2,5-dione (anti-depressant) (anti-tumor) (antimicrobial) O


Page 3 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 1. Synthetic methods for synthesis of piperazines a) biocatalytic synthesis from 1,2-dicarbonyl and 1,2-diamine substrates10a R1 R3 2 R6 R IRED R1 O HN R4 N + N R3 R5 2 R O HN R5 4 R 2 NADPH + 2 H+ 2 NADP+ R6 b) Using SnAP reagents and aldehydes using continuous flow photo-chemistry10b Boc NBoc Iridium catalyst N SnBu3 O + HN blue LEDs R H flow reactor NH2 R c) palladium-catalyzed synthesis from propargyl carbonates and bis-nitrogen nucleophiles10f OBoc H Ts N Ts N Ts N Pd2(dba)3.CHCl3 H N DPEphos, CH2Cl2 Ts

In the recent years, small ring aza-hetereocycles have become one of the useful building blocks for the synthesis of various N-heterocyclic scaffolds.11 For more than a decade and half, our group has been involved in the synthetic and mechanistic exploration of SN2-type ring-opening transformations of N-activated aziridines and azetidines for the synthesis of a wide array of Nheterocycles of bio- and pharmacological relevance via ring-opening cyclization (ROC) or by domino ring-opening cyclization (DROC) strategies.12 We recently reported the synthesis of 3spiropiperidino indolenines via Lewis-acid catalyzed ring-opening of activated aziridines with 1Hindoles followed by Pd-catalyzed dearomative spirocyclization with propargyl carbonates (Scheme 2).12a Based on our recent results, earlier experiences, and in continuation of our research activities in this area, we anticipated that highly substituted piperazines could easily be synthesized via ring-opening of activated aziridines with anilines followed by Pd-catalyzed annulation with propargyl carbonates.13 In this article, we report our results in detail.



Page 4 of 32

Scheme 2. Synthesis of 3-spiropiperidino indolenines via Lewis-acid catalyzed ring-opening of activated aziridines with 1H-indoles followed by Pd-catalyzed dearomative spirocyclization with propargyl carbonates.

Ts N + Ph

Ph Ph N H

HN Ts O

LiClO4 CH3CN

Ph N H

Ts N

Boc

Pd(PPh3)4 BINAP 1,2-DCE

Ph Ph N

Results and Discussion Our study began with the reaction of 2-phenyl-N-tosylaziridine (1a), aniline (2a) and tert-butyl prop-2-yn-1-yl carbonate (3a). Aziridine 1a was reacted with 2a in neat conditions at room temperature and the corresponding ring-opening product was then treated with 3a in the presence of Pd(dba)2 and Xantphos ligand in CH2Cl2 at room temperature. Workup with 10% dil. HCl afforded the desired product 4a (38%) along with some amount of the isomerized product 4a' (10%) (Scheme 3). To control the isomerization of the product from 4a to 4a', the acidic workup was excluded and to our delight, the desired product, 2-methylene-4,5-diphenyl-1-tosylpiperazine (4a) was obtained as a single isomer in 54% yield in 10 h (entry 1, Table 1). Use of Pd(PPh3)4 instead of Pd(dba)2 improved the yield to 63% (entry 2, Table 1). Various solvents were tested and the best yield was obtained in DMSO as the solvent (71%) in 15 minutes at rt (entry 4, Table 1). The reaction time was reduced to 5 minutes and yield improved to 78% when the reaction was carried out at 120 °C (entry 7, Table 1). A number of ligands were screened and (±)-BINAP was found to be the best one for the reaction (entry 12, Table 1). The reaction


Page 5 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 3. Ring opening of 2-phenyl-N-tosylaziridine 1a with aniline 2a followed by Pd-catalyzed cyclization with propargyl tert-butyl carbonate 3a Ts N

NH2 i) rt, 1.5 h ii)

Ph

1a 2a (1.0 equiv) (3.0 equiv)

N

Boc N O Ts 3a (1.3 equiv) 4a Pd(dba)2, Xantphos CH2Cl2, rt, 10 h

Ph Ph

N Ts

N

Ph Ph

4a'

did not proceed at all when the combination of Pd(OAc)2 and PPh3 was used (entry 16, Table 1). The reaction became sluggish with reduced amount of Pd source and the ligand (entry 17, Table 1). The best result was obtained with 0.1 equiv of Pd(PPh3)4, 0.2 equiv of (±)-BINAP in dry DMSO solvent at 120 °C. When ring opening product was first isolated then cyclized in the next step, the piperazine 4a was obtained with a reduced overall yield (72%). The structure of the compound 4a was ascertained by spectroscopic data and the structure was further confirmed by X-ray crystallographic analysis (See supporting information).13 Table 1. Optimization studies for the one-pot synthesis of 2-methylene-4,5-diphenyl-1tosylpiperazine 4aa NH2

Ts N

i) rt, 1.5 h ii)

Ph 1a (1.0 equiv)

2a (3.0 equiv)

O

Boc 3a (1.3 equiv)

N Ts

N

Ph Ph

4a

Pd source, ligand solvent, temp, time

entry Pd source

ligand

solvent

temp (°C) time

Yield (%)

1

Pd(dba)2

Xantphos

DCM

Rt

10 h

54

2

Pd(PPh3)4

Xantphos

DCM

Rt

10 h

63

3

Pd(PPh3)4

Xantphos

1,2-DCE

Rt

10 h

54



Page 6 of 32

4

Pd(PPh3)4

Xantphos

DMSO

Rt

15 min

71

5b

Pd(PPh3)4

Xantphos

DMSO

Rt

15 min

70

6

Pd(PPh3)4

Xantphos

1,2-DCE

80

30 min

71

7

Pd(PPh3)4

Xantphos

DMSO

120

5 min

78

8

Pd(PPh3)4

Xantphos

CH3CN

80

1 h 20 min

69

9

Pd(PPh3)4

Xantphos

DMF

120

30 min

65

10

Pd(PPh3)4

Xantphos

Toluene

120

1h

69

11

Pd(PPh3)4

Xantphos

THF

70

30 min

61

12

Pd(PPh3)4 (±)-BINAP DMSO

120

5 min

83

13

Pd(PPh3)4

Dppf

DMSO

120

5 min

70

14

Pd(PPh3)4

Xphos

DMSO

120

45 min

74

15

Pd(PPh3)4

P(o-tolyl)3

DMSO

120

5 min

78

16

Pd(OAc)2

PPh3

DMSO

120

–

NR

17c

Pd(PPh3)4

(±)-BINAP

DMSO

120

3h

60

18d

Pd(PPh3)4

(±)-BINAP

DMSO

120

5 min

72

aUnless

noted otherwise, 1.0 equiv of 1a, 3.0 equiv of 2a and 1.3 equiv of 3a were used in all the

cases with 0.1 equiv of the Pd source, 0.2 equiv of the ligand in 1.5 mL of the solvent. bThe reaction was carried out in the presence of 1.5 equiv of Cs2CO3. cThe reaction was performed with 0.05 equiv of Pd source and 0.1 equiv of the ligand. dThe ring-opened product was isolated and then cyclized with propargyl carbonate to yield 4a in two-pot stepwise manner.


Page 7 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


To generalize our approach, a number of aziridines (1b–f) were studied. The results are detailed in Table 2. The best result was obtained with 2-(3-fluorophenyl)-N-tosylaziridine (1c) (entry 3, Table 2). Table 2. Substrate scope with respect to aziridinesa NH2

SO2Ar2 N + Ar

i) rt, 1.5 h ii)

1

1a-f

Aziridine 1

Ph

3

1a

1b

Ts

1c

4

1d

CF3

83%

Ph Br

66%

Ts

F

91%

Ph

N 4c

N Ts

Ph

N

64% 4d

1e

Yield

4b

N

Me

N Ts

Ph

N

70% F3C 4e


Ph Ar1

Ph

N

Me

Ts N

N 4a-f

Ph

4a

N

Ts N

5

N

Ts

Ts N F

Ar2O2S

N

Ts N Br

3a

Product 4

Ts N

1

2

OBoc

Pd(PPh3)4, ()-BINAP DMSO, 120 C, 5-30 min

2a

Entry

N


Page 8 of 32

MeO N

Ph aUnless

O

SO2 N

6

S O

N

Ph

64%

Ph 4f

MeO

1f

otherwise stated, all the reactions were carried out using 1.0 equivalent of aziridine 1, 3.0

equivalents of aniline 2a and 1.3 equivalents of 3a in the presence of 0.1 equivalent of Pd(PPh3)4 and 0.2 equivalent of (±)-BINAP.

Further generalization of the strategy was made by studying different anilines with 1a. The reaction went smoothly with anilines having 3-bromo (2b), 4-methyl (2c), 4-tert-butyl (2d), 4-fluoro (2e) and 3-chloro (2f) substituents to furnish the corresponding piperazines 4g–k in very good yields (Table 3). Table 3. Substrate scope with respect to substituted anilinesa Ts N

NH2 +

R

Ph 1a

i) rt, 1.5 h

1

Ts

Pd(PPh3)4, ()-BINAP DMSO, 120 C, 5-30 min

2

Entry

N

OBoc 3a

ii)

Aniline 2

Product 4

Yield 81% Br

N Br

Ts

N

Ph 4g


R Ph

4

NH2

2b

N

Page 9 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2

83%

NH2 N Ts

Me 2c

3

N

Ph

4h

81%

NH2

N Ts

N

4

Ph

4i

2d NH2

F

74%

N Ts

F

N

Ph

4j

2e

5

78%

NH2 Cl

N

Cl 2f aUnless

Ts

N 4k

Ph

noted otherwise, all the reactions were carried out using 1.0 equivalent of aziridine 1a, 3.0

equivalents of aniline 2 and 1.3 equivalents of 3a in the presence of 0.1 equivalent of Pd(PPh3)4 and 0.2 equivalent of (±)-BINAP.

Next, the reaction was performed with tert-butyl(3-phenylprop-2-yn-1-yl)carbonate (3b) and isomeric tert-butyl-(1-phenylprop-2-yn-1-yl)carbonate (3c) and interestingly, (Z)-2-benzylidene4,5-diphenyl-1-tosylpiperazine (4l) was obtained in both the cases, suggesting the intermediacy of the Pd-π-allyl complex (Scheme 4).



Page 10 of 32

Scheme 4. Reaction of 2-phenyl-N-tosyl aziridine 1a with aniline 2a followed by cyclization with substituted propargyl carbonates Ts N

NH2 i) rt, 1.5 h

+

R1

ii)

Ph 1a 2a (1.0 equiv) (3.0 equiv) 3b: R1 = Ph, R2 = H 3c: R1 = H, R2 = Ph

R2

Ph

3 (1.3 equiv) OBoc

Pd(PPh3)4 (0.1 equiv) (±)-BINAP (0.2 equiv) DMSO, 120 °C

N Ts

N

Ph 4

4l, 65%, 5 min 4l, 64%, 10 min

The synthetic utility of the methodology was further shown by the syntheses of fused piperazine derivatives employing the cycloalkane-fused aziridines. When cyclohexyl (1g) and cyclopentyl (1h) aziridines were reacted with different anilines and propargyl carbonates, the corresponding fused piperazine derivatives were obtained in very good yields (up to 88%) (Table 4). Table 4. Substrate scope of cyclic fused aziridines Ts N

NH2 +

Aziridine 1

1

Ts N

1h

R2

ii)

R1

( )n 2 1g-h (1.0 equiv) (3.0 equiv)

Entry

R1

i) rt, 45 min-1.5 h

Pd(PPh3)4 (0.1 equiv) ()-BINAP (0.2 equiv) DMSO, 120 °C, 5 min

Aniline 2

N

3 (1.3 equiv) OBoc

Propargyl carbonate 3

NH2

OBoc 3a

2a


R2

( )n

N Ts 4k-o

Product 4 Ph N N Ts 4m

Yield 88%

Page 11 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2

Ts N

1g

3

NH2

Ph N

OBoc 3a

N Ts 4n

2a

Ts N

NH2

1h

Me 2c

77%

Me

OBoc

79%

3a

N N Ts 4o

4

Ts N

NH2

72%

OBoc 3a

1g

N

2d

N Ts 4p

5

Ts N

NH2

Ph

Me

80%

OBoc 3b

1g

Me 2c

N

Ph

N Ts 4q

The synthetic significance of the strategy was demonstrated by the synthesis of enantiopure 2methylene-4,5-diphenyl-1-tosylpiperazine

((S)-4a)

and

(Z)-2-benzylidene-4,5-diphenyl-1-

tosylpiperazine ((S)-4l) via ring-opening of enantiopure aziridine ((R)-1a) with aniline followed



Page 12 of 32

by cyclization with tert-butyl prop-2-yn-1-yl carbonate (3a) and tert-butyl(3-phenylprop-2-yn-1yl)carbonate (3b), respectively (Scheme 5). Scheme 5. Enantiospecific synthesis of piperazine derivatives from enantiopure 2-phenyl-Ntosylaziridine Ts N

NH2

i) rt, 1.5 h

+ ii)

Ph

R1

OBoc 3 (1.3 equiv) Pd(PPh3)4 (0.1 equiv) (±)-BINAP (0.2 equiv) DMSO, 120 °C, 5 min R1 = H, 3a; R1 = Ph, 3b

2a (R)-1a ee >99% (3.0 equiv) (1.0 equiv)

Entry

Aziridine 1

Aniline 2

1

(R)-1a

2

(R)-1a

R1

N N

Ts

4

Product 4

Yield

Ee

2a

Propargyl carbonate 3 3a

(S)-4a

81%

> 99%

2a

3b

(S)-4l

65%

> 99%

A plausible mechanism of the reaction is shown in Scheme 6. The 2-aryl-N-sulfonyl aziridine 1 readily undergoes ring-opening with aniline via an SN2 pathway to form the corresponding ringopening product A. Then, the propargyl carbonate under the action of Pd-catalyst undergoes decarboxylative oxidative addition to form the Pd-π-allyl complex B. Then the in situ generated tert-butoxide ion abstracts a proton from the ring-opened product A to form the negatively-charged intermediate C. The intermediate C then attacks the cationic complex B to form the Pd-carbenoid species D which further undergoes proton migration to form the Pd-π-allyl species E. The species E undergoes cyclization followed by reductive elimination to furnish the piperazine product 4. Scheme 6. Mechanistic pathway for the synthesis of 1,4-piperazines 4 via ring-opening of Nactivated aziridine 1 with aniline 2 and subsequent cyclization with propargyl carbonate 3


Page 13 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


SO2Ar1 N Ar2

N Ar1O2S

N

Ar

Ar NH2

1

Ar

N E

Ar2

H N

3 Pd(0)Ln reductive elimination

N H

Ar2 A

SO2Ar1

OBoc CO2 + OtBu tBuOH

decarboxylative oxidative addition Pd(II)

B

Pd(II) Ar3

3

2

3

Ar2

4

3

SN2-type ring-opening

Ar

3

H N

N

SO2Ar1

Ar2 C

N SO2Ar1 LnPd Ar3 D

H N Ar2

N SO2Ar1

Conclusion In conclusion, we have developed an efficient three-component and highly diastereo- and enantioselective synthetic route to medicinally important piperazine derivatives via SN2-type ringopening of 2-aryl-N-sulfonylaziridines with anilines followed by cyclization with propargyl carbonates under one-pot stepwise three component coupling strategy. The synthesized piperazine derivatives possess an exocyclic double bond which could easily be synthetically manipulated for desired functionalization. We strongly believe that this methodology will be very useful for the pharmacological industry and synthetic organic chemists. Experimental Section General Procedures. The analytical thin layer chromatography (TLC) was carried out for monitoring the progress of the reactions using silica gel 60 F254 precoated plates. Visualizations of the spots were accomplished with a UV lamp or I2 stain. Active Aluminium oxide was used for



Page 14 of 32

flash column chromatographic purification using a combination of distilled ethyl acetate and petroleum ether as the eluent. Unless otherwise mentioned, all of the reactions were carried out in oven-dried glassware under an atmosphere of nitrogen or argon using anhydrous solvents. Where appropriate, the solvents and all of the reagents were purified prior to use following the guidelines of

Armarego

and

Chai.15

The

monosubstituted

N-tosylaziridines

(1a–e)16

and

N-

arylsulfonylaziridines (1f)17 were prepared by following the earlier reports. The propargyl carbonates (3a–c) were also prepared by following an earlier report.18 All of the commercial reagents were used as received without further purification unless otherwise mentioned. Proton nuclear magnetic resonance (1H NMR) spectra were recorded at 400 MHz and 500 MHz. The chemical shifts were recorded in parts per million (ppm, δ) using tetramethylsilane (δ 0.00) as the internal standard. Splitting patterns of the 1H NMR are mentioned as singlet (s), doublet (d), doublet of doublets (dd), doublet of doublet of doublets (ddd), triplet (t), triplet of doublets (td), multiplet (m) etc. Proton-decoupled carbon nuclear magnetic resonance (13C{1H} NMR) spectra were recorded at 100 MHz and 125 MHz. HRMS were obtained using (ESI) mass spectrometer (TOF). KBr pellets were used for IR spectra of solid compounds. The melting point measurements were made using a hot stage apparatus and are reported as uncorrected. The enantiomeric excess (ee) was determined by chiral HPLC with Chiralcel OD-H and Chiralpak AD-H (detection at 254 nm) using hexane and isopropanol as the mobile phase and an UV/VIS detector. Optical rotations were measured using a 6.0 mL cell with a 1.0 dm path length and are reported as [α]25D (c in g per 100 mL solvent) at 25 °C. General procedure for ring-opening of aziridines with anilines followed by cyclization with propargyl carbonates. The aziridine (1.0 equiv) and aniline (3.0 equiv) were stirred at room temperature until complete consumption of aziridine. After the complete consumption of aziridine,


Page 15 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Pd(PPh3)4 (0.1 equiv), (±)-BINAP (0.2 equiv) and propargylic carbonate (1.3 equiv) in 2.0 mL of dry DMSO were added. The reaction mixture was then immediately heated at 120 °C. The progress of the reaction was monitored by TLC and after completion, the reaction mixture was filtered through a small plug of activated aluminium oxide followed by concentration under reduced pressure. The crude product was purified by flash column chromatography on activated aluminium oxide using ethyl acetate in petroleum ether as the eluent to afford the corresponding piperazine derivatives. (S)-2-methylene-4,5-diphenyl-1-tosylpiperazine (4a). The general method described above was followed when 1a (50.0 mg, 0.183 mmol, 1.0 equiv) was reacted with 2a (50 μL, 0.548 mmol, 3.0 equiv) followed by reaction with 3a (37.1 mg, 0.237 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (21.1 mg, 0.018 mmol, 0.1 equiv) and (±)-BINAP (22.7 mg, 0.036 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4a (61.0 mg, 0.151 mmol) as white solid in 83% yield. mp 120–122 °C; [α]25D +57.0 (c 0.466 in CH2Cl2) for a >99% ee sample. Optical purity was determined by chiral HPLC analysis (Chiralcel OD-H column), hexane–isopropanol, 90:10; flow rate = 1.0 mL/min; tR 1: 11.7 min (minor), tR 2: 29.2 min (major); Rf 0.50 (EtOAc : petroleum ether, 2:8); IR ν̃max (KBr, cm−1) 3061, 3029, 2923, 1668, 1597, 1500, 1452, 1382, 1346, 1250, 1223, 1184, 1162, 1102, 1048, 1018, 993, 976, 870, 813, 749, 706, 680, 643, 582, 557, 544, 506 ; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 2H, J = 7.9 Hz), 7.34–7.24 (m, 5H), 7.07–7.00 (m, 4H), 6.68 (t, 1H, J = 7.3 Hz), 6.44 (d, 2H, J = 7.9 Hz), 5.19 (s, 1H), 4.67 (s, 1H), 4.62–4.59 (m, 1H), 4.36–4.40 (m, 1H), 4.06–3.98 (m, 2H), 3.73 (dd, 1H, J = 14.0, 7.9 Hz), 2.30 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 148.7, 143.8, 140.1, 139.1, 135.3, 129.3, 128.96, 128.93, 127.7, 127.1, 126.1, 118.0, 113.2, 98.8, 61.6, 50.3, 49.1, 21.4; HRMS (ESI-TOF) calcd for C24H25N2O2S (M + H)+ 405.1637, found 405.1635.



2-(3-bromophenyl)-5-methylene-1-phenyl-4-tosylpiperazine (4b). The general method described above was followed when 1b (50.0 mg, 0.142 mmol, 1.0 equiv) was reacted with 2a (39 μL, 0.426 mmol, 3.0 equiv) followed by reaction with 3a (28.8 mg, 0.184 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (16.4 mg, 0.014 mmol, 0.1 equiv) and (±)-BINAP (17.7 mg, 0.028 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4b (44.4 mg, 0.092 mmol) as a thick liquid in 66% yield. Rf 0.38 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 3059, 2922, 1638, 1597, 1570, 1501, 1473, 1425, 1344, 1251, 1224, 1185, 1163, 1091, 1069, 1035, 995, 975, 945, 884, 812, 784, 749, 705, 689, 679, 662, 643, 595, 547, 507; 1H NMR (500 MHz, CDCl3) δ 7.50–7.39 (m, 4H), 7.25–7.17 (m, 2H), 7.09–7.03 (m, 4H), 6.71 (t, 1H, J = 7.3 Hz), 6.42 (d, 2H, J = 8.0 Hz), 5.22 (s, 1H), 4.69 (s, 1H), 4.58–4.56 (m, 1H), 4.34 (dd, 1H, J = 13.8, 5.1 Hz), 4.03–3.97 (m, 2H), 3.75–3.70 (m, 1H), 2.31 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 148.5, 144.0, 142.9, 138.8, 135.1, 130.8, 130.5, 129.4, 129.2, 129.0, 127.0, 124.8, 123.1, 118.4, 113.2, 99.0, 61.4, 50.1, 49.1, 21.5; HRMS (ESITOF) calcd for C24H24BrN2O2S (M + H)+ 483.0742, found 483.0745. 2-(3-fluorophenyl)-5-methylene-1-phenyl-4-tosylpiperazine (4c). The general method described above was followed when 1c (50.0 mg, 0.171 mmol, 1.0 equiv) was reacted with 2a (47 μL, 0.514 mmol, 3.0 equiv) followed by reaction with 3a (34.7 mg, 0.222 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (19.8 mg, 0.017 mmol, 0.1 equiv) and (±)-BINAP (21.3 mg, 0.034 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4c (65.9 mg, 0.156 mmol) as a semi-solid in 91% yield. Rf 0.47 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 2922, 1638, 1597, 1502, 1448, 1344, 1263, 1221, 1185, 1162, 1092, 1035, 948, 871, 812, 785, 749, 707, 690, 674, 647, 597, 547, 507; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 2H, J = 8.5 Hz), 7.32–7.24 (m, 1H), 7.10–6.93 (m, 7H), 6.72– 6.69 (m, 1H), 6.42 (d, 2H, J = 7.9 Hz), 5.22 (s, 1H), 4.69 (s, 1H), 4.61–4.58 (m, 1H), 4.36–4.31 (m, 1H), 3.99 (s, 2H), 3.74 (dd, 1H, J = 14.0, 7.9 Hz), 2.31 (s, 3H); 13C{1H} NMR (100 MHz,


Page 16 of 32

Page 17 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


CDCl3) δ 163.3 (d, 1JC–F = 246.3 Hz), 148.6, 144.1, 143.3, 143.2, 138.9, 135.2, 130.6, 130.5, 129.5, 129.1, 127.1, 121.7, 118.4, 114.8, 114.6, 113.5, 113.3, 113.2, 99.3, 61.4, 50.2, 49.2, 21.6; 19F NMR (400 MHz, CDCl3) δ −112.00(s). HRMS (ESI-TOF) calcd for C24H24FN2O2S (M + H)+ 423.1543, found 423.1554. 2-methylene-4-phenyl-5-(p-tolyl)-1-tosylpiperazine (4d). The general method described above was followed when 1d (50.0 mg, 0.174 mmol, 1.0 equiv) was reacted with 2a (48 μL, 0.522 mmol, 3.0 equiv) followed by reaction with 3a (35.3 mg, 0.226 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (20.1 mg, 0.017 mmol, 0.1 equiv) and (±)-BINAP (21.7 mg, 0.035 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4d (46.4 mg, 0.111 mmol) as a colorless solid in 64% yield. mp 132– 135 °C; Rf 0.50 (EtOAc : petroleum ether, 2:8); IR ν̃max (KBr, cm−1) 2922, 1667, 1596, 1500, 1381, 1346, 1250, 1161, 1097, 1051, 975, 873, 812, 748, 708, 688, 666, 638, 588, 544; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H, J = 8.5 Hz), 7.18–7.10 (m, 4H), 7.06–6.99 (m, 4H), 6.67 (t, 1H, J = 7.3 Hz), 6.42 (d, 2H, J = 7.9 Hz), 5.18 (s, 1H), 4.65 (s, 1H), 4.59–4.55 (m, 1H), 4.35 (dd, 1H, J = 14.0, 5.4 Hz), 4.00 (d, 2H, J = 1.8 Hz), 3.70 (dd, 1H, J = 14.0, 7.9 Hz), 2.33 (s, 3H), 2.29 (s, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 148.9, 143.9, 139.3, 137.4, 137.2, 135.3, 129.7, 129.4, 129.0,

127.2, 126.0, 118.0, 113.3, 98.8, 61.4, 50.5, 49.1, 21.6, 21.2; HRMS (ESI-TOF) calcd for C25H27N2O2S (M + H)+ 419.1793, found 419.1786. 2-methylene-4-phenyl-1-tosyl-5-(2-(trifluoromethyl)phenyl)piperazine (4e). The general method described above was followed when 1e (50.0 mg, 0.147 mmol, 1.0 equiv) was reacted with 2a (40 μL, 0.439 mmol, 3.0 equiv) followed by reaction with 3a (29.8 mg, 0.190 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (16.9 mg, 0.015 mmol, 0.1 equiv) and (±)-BINAP (18.3 mg, 0.029 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4e (41.6 mg, 0.088 mmol) as a semi-solid in 60% yield. Rf 0.40 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 3040, 2924, 2854, 1639, 1598, 1503,



1454, 1348, 1310, 1285, 1259, 1225, 1163, 1116, 1092, 1059, 1037, 996, 943, 910, 879, 812, 769, 749, 710, 692, 674, 652, 602, 575, 548, 510; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, 1H, J = 7.3 Hz), 7.59 (d, 3H, J = 8.5 Hz), 7.43–7.34 (m, 2H), 7.04–6.99 (m, 4H), 6.68 (t, 1H, J = 7.3 Hz), 6.42 (d, 2H, J = 7.9 Hz), 5.35 (s, 1H), 4.88–4.84 (m, 1H), 4.73 (s, 1H) 4.49–4.44 (m, 1H), 4.16–4.02 (m, 2H), 3.64–3.59 (m, 1H), 2.27 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 148.6, 144.0, 139.8, 139.5, 135.6, 132.7, 129.4, 129.0, 128.5, 128.0, 127.1, 126.6, 126.5, 119.0, 114.2, 99.0, 58.6, 50.3, 21.6; 19F NMR (400 MHz, CDCl3) δ −58.11(s). HRMS (ESI-TOF) calcd for C25H24F3N2O2S (M + H)+ 473.1511, found 473.1521. 1-((4-methoxyphenyl)sulfonyl)-2-methylene-4,5-diphenylpiperazine (4f). The general method described above was followed when 1f (50.0 mg, 0.173 mmol, 1.0 equiv) was reacted with 2a (47 μL, 0.518 mmol, 3.0 equiv) followed by reaction with 3a (35.1 mg, 0.224 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (19.9 mg, 0.017 mmol, 0.1 equiv) and (±)-BINAP (21.5 mg, 0.035 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4f (46.2 mg, 0.110 mmol) as a semi-solid in 64% yield. Rf 0.40 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 3061, 3028, 2924, 2853, 1670, 1596, 1579, 1497, 1455, 1413, 1381, 1346, 1308, 1259, 1180, 1157, 1091, 1026, 993, 976, 907, 870, 833, 804, 751, 718, 699, 681, 646, 628, 581, 559; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, 2H, J = 8.5 Hz), 7.33–7.25 (m, 5H), 7.07–7.04 (m, 2H), 6.69–6.66 (m, 3H), 6.44 (d, 2H, J = 8.0 Hz), 5.19 (s, 1H), 4.67 (s, 1H), 4.63–4.60 (m, 1H), 4.41–4.37 (m, 1H), 4.07–3.99 (m, 2H), 3.77–3.70 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 163.0, 148.8, 140.2, 139.2, 129.2, 128.9, 128.7, 127.7, 126.0, 118.0, 113.8, 113.1, 98.6, 61.6, 55.3, 50.2, 48.9, ; HRMS (ESI-TOF) calcd for C24H25N2O3S (M + H)+ 421.1586, found 421.1585. 1-(3-bromophenyl)-5-methylene-2-phenyl-4-tosylpiperazine (4g). The general method described above was followed when 1a (50.0 mg, 0.183 mmol, 1.0 equiv) was reacted with 2b (92 μL, 0.549


Page 18 of 32

Page 19 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


mmol, 3.0 equiv) followed by reaction with 3a (37.1 mg, 0.238 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (21.1 mg, 0.018 mmol, 0.1 equiv) and (±)-BINAP (22.7 mg, 0.036 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4g (71.0 mg, 0.147 mmol) as a semi-solid in 81% yield. Rf 0.39 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 2923, 2853, 1640, 1592, 1557, 1484, 1451, 1345, 1227, 1197, 1163, 1092, 1027, 937, 885, 812, 760, 699, 681, 660, 644, 596, 547; 1H NMR (500 MHz, CDCl3) δ 7.51 (d, 1H, J = 8.3 Hz), 7.36–7.25 (m, 5H), 7.01 (d, 2H, J = 8.1 Hz), 6.87– 6.84 (m, 1H), 6.77–6.75 (m, 1H), 6.47–6.46 (m, 1H), 6.29–6.27 (m, 1H), 5.30 (s, 1H), 4.71 (s, 1H), 4.57–4.55 (m, 1H), 4.47 (dd, 1H, J = 14.1, 5.7 Hz), 3.98 (s, 2H), 3.63 (dd, 1H, J = 14.1, 8.7 Hz), 2.30 (s, 3H) ; 13C{1H} NMR (125 MHz, CDCl3) δ 150.0, 144.0, 139.3, 138.8, 135.1, 130.1, 129.3, 129.1, 127.9, 127.0, 125.7, 123.0, 120.7, 115.6, 111.7, 99.3, 61.3, 49.9, 48.3, 21.5; HRMS (ESI-TOF) calcd for C24H24BrN2O2S (M + H)+ 483.0742, found 483.0749. 2-methylene-5-phenyl-4-(p-tolyl)-1-tosylpiperazine (4h). The general method described above was followed when 1a (50.0 mg, 0.183 mmol, 1.0 equiv) was reacted with 2c (60 μL, 0.549 mmol, 3.0 equiv) followed by reaction with 3a (37.1 mg, 0.238 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (21.1 mg, 0.018 mmol, 0.1 equiv) and (±)-BINAP (22.7 mg, 0.036 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4h (63.6 mg, 0.152 mmol) as a semi-solid in 83% yield. Rf 0.62 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 3061, 3028, 2922, 2856, 1742, 1638, 1617, 1598, 1573, 1518, 1493, 1452, 1346, 1306, 1276, 1230, 1185, 1163, 1131, 1092, 1028, 1018, 946, 913, 884, 860, 809, 755, 738, 701, 666, 646, 636, 607, 584, 547, 508; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, 2H, J = 7.9 Hz), 7.32–7.24 (m, 5 H), 7.04 (d, 2H, J = 7.9 Hz), 6.86 (d, 2H, J = 8.5 Hz), 6.38 (d, 2H, J = 9.1 Hz), 5.19 (s, 1H), 4.68 (s, 1H), 4.56 (dd, 1H, J = 7.9, 4.8 Hz), 4.36 (dd, 1H, J = 14.0, 4.8 Hz), 3.96 (s, 2H), 3.72-3.67 (m, 1H), 2.31 (s, 3H), 2.19 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 146.7, 143.8, 140.3, 139.3, 135.5, 129.4, 129.3, 128.8, 127.6, 127.1, 126.2, 114.0,



99.1, 61.7, 50.5, 50.0, 21.4, 20.2; HRMS (ESI-TOF) calcd for C25H27N2O2S (M + H)+ 419.1793, found 419.1798. 1-(4-(tert-butyl)phenyl)-5-methylene-2-phenyl-4-tosylpiperazine (4i). The general method described above was followed when 1a (50.0 mg, 0.183 mmol, 1.0 equiv) was reacted with 2d (87 μL, 0.549 mmol, 3.0 equiv) followed by reaction with 3a (37.1 mg, 0.238 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (21.1 mg, 0.018 mmol, 0.1 equiv) and (±)-BINAP (22.7 mg, 0.036 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4i (69.0 mg, 0.150 mmol) as a semi-solid in 81% yield. Rf 0.54 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 3031, 2960, 2867, 1639, 1612, 1518, 1493, 1452, 1347, 1266, 1226, 1196, 1164, 1092, 1028, 945, 885, 813, 700, 660, 603, 579, 547; 1H

NMR (400 MHz, CDCl3) δ 7.49 (d, 2H, J = 8.4 Hz), 7.33–7.24 (m, 5H), 7.13 (d, 2H, J = 8.5

Hz), 7.06 (d, 2H, J = 8.5 Hz), 6.46 (d, 2H, J = 9.1 Hz), 5.12 (s, 1H), 4.65 (s, 1H), 4.61–4.58 (m, 1H), 4.29 (dd, 1H, J = 13.4, 4.8 Hz), 4.02 (s, 2H), 3.83–3.78 (m, 1H), 2.33 (s, 3H), 1.24 (s, 9H); 13C{1H}

NMR (125 MHz, CDCl3) δ 146.4, 143.7, 140.8, 140.5, 139.1, 135.4, 129.48, 129.40,

128.8, 128.7, 127.6, 127.4, 127.2, 127.0, 126.5, 126.2, 125.8, 115.6, 113.0, 98.4, 61.8, 50.4, 49.6, 33.7, 31.4, 21.5; HRMS (ESI-TOF) calcd for C28H33N2O2S (M + H)+ 461.2263, found 461.2268. 1-(4-fluorophenyl)-5-methylene-2-phenyl-4-tosylpiperazine (4j). The general method described above was followed when 1a (50.0 mg, 0.183 mmol, 1.0 equiv) was reacted with 2e (52 μL, 0.549 mmol, 3.0 equiv) followed by reaction with 3a (37.1 mg, 0.238 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (21.1 mg, 0.018 mmol, 0.1 equiv) and (±)-BINAP (22.7 mg, 0.036 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4j (58.5 mg, 0.138 mmol) as a semi-solid in 76% yield. Rf 0.34 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 3058, 3028, 2923, 2853, 1639, 1597, 1509, 1452, 1346, 1228, 1197, 1164, 1092, 1028, 1018, 939, 884, 812, 757, 702, 665, 632, 607, 583, 547; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, 2H, J = 8.0 Hz), 7.34–7.25 (m, 5H), 7.05 (d, 2H, J =


Page 20 of 32

Page 21 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


8.0 Hz), 6.74–6.71 (m, 2H), 6.39 (dd, 2H, J = 9.1, 4.5 Hz), 5.24 (s, 1H), 4.69 (s, 1H), 4.48 (dd, 1H, J = 8.5, 5.1 Hz), 4.41 (dd, 1H, J = 13.7, 5.1 Hz), 3.97–3.88 (m, 2H), 3.59 (dd, 1H, J = 13.7, 9.1 Hz), 2.32 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 155.5, 145.8, 144.1, 140.0, 139.3, 135.5, 129.4, 129.0, 127.9, 127.2, 126.2, 115.5, 115.4, 115.3, 99.6, 62.5, 50.4, 21.5; 19F NMR (400 MHz, CDCl3) δ −122.7 (s), −126.1 (s). HRMS (ESI-TOF) calcd for C24H24FN2O2S (M + H)+ 423.1543, found 423.1548. 1-(3-chlorophenyl)-5-methylene-2-phenyl-4-tosylpiperazine (4k). The general method described above was followed when 1a (50.0 mg, 0.183 mmol, 1.0 equiv) was reacted with 2e (58 μL, 0.549 mmol, 3.0 equiv) followed by reaction with 3a (37.1 mg, 0.238 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (21.1 mg, 0.018 mmol, 0.1 equiv) and (±)-BINAP (22.7 mg, 0.036 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4k (62.0 mg, 0.141 mmol) as a semi-solid in 78% yield. Rf 0.36 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 2921, 1640, 1594, 1563, 1487, 1451, 1345, 1227, 1163, 1092, 1028, 986, 938, 885, 812, 761, 729, 700, 666, 645, 597, 547; 1H NMR (500 MHz, CDCl3) δ 7.51 (d, 2H, J = 8.0 Hz), 7.36–7.25 (m, 5H), 7.00 (d, 2H, J = 8.0 Hz), 6.92 (t, 1H, J = 8.0 Hz), 6.31–6.61 (m, 1H), 6.30 (t, 1H, J = 2.2 Hz), 6.25 (dd, 2H, J = 8.5, 2.2 Hz), 5.30 (s, 1H), 4.71 (s, 1H), 4.56 (dd, 1H, J = 8.5, 6.3 Hz), 4.47 (dd, 1H, J = 14.3, 5.7 Hz), 3.99 (s, 2H), 3.64 (dd, 1H, J = 14.3, 8.5 Hz), 2.29 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 149.9, 144.1, 139.4, 138.9, 135.2, 134.8, 129.9, 129.4, 129.2, 128.0, 127.1, 125.8, 117.8, 112.9, 111.2, 99.3, 61.4, 49.9, 48.2, 21.7; HRMS (ESI-TOF) calcd for C24H24ClN2O2S (M + H)+ 439.1247, found 439.1250.(S,Z)-2-benzylidene-4,5-diphenyl-1-tosylpiperazine (4l). The general method described above was followed when 1a (50.0 mg, 0.183 mmol, 1.0 equiv) was reacted with 2a (50 μL, 0.548 mmol, 3.0 equiv) followed by reaction with 3b (55.4 mg, 0.237 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (21.1 mg, 0.018 mmol, 0.1 equiv) and (±)-BINAP (22.7 mg, 0.036 mmol, 0.2 equiv)



in DMSO (2.0 mL) to afford 4l (68.2 mg, 0.142 mmol) as white solid in 78% yield. mp 151–153 °C; [α]25D −77.2 (c 0.416 in CH2Cl2) for a >99% ee sample. Optical purity was determined by chiral HPLC analysis (Chiralpak AD-H column), hexane–isopropanol, 90:10; flow rate = 1.0 mL/min; tR 1: 45.17 min (major), tR 2: 70.25 min (minor); Rf 0.45 (EtOAc : petroleum ether, 2:8); IR ν̃max (KBr, cm−1) 3026, 2923, 1633, 1597, 1493, 1451, 1343, 1305, 1237, 1165, 1090, 1028, 997, 950, 871, 812, 753, 727, 699, 677, 666, 648, 616, 560, 548, 528; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, 2H, J = 7.9 Hz), 7.44 (d, 2H, J = 7.3 Hz), 7.32–7.28 (m, 4H), 7.24–7.12 (m, 6H), 7.07 (dd, 2H, J = 7.3, 8.5 Hz), 6.75 (t, 1H, J = 7.3 Hz), 6.68 (d, 2H, J = 7.9 Hz), 5.50 (s, 1H), 5.18 (s, 1H), 4.90 (dd, 1H, J = 3.0, 11.6 Hz), 4.62 (s, 1H), 4.15 (dd, 1H, J = 3.0, 12.8 Hz), 3.29 (dd, 1H, J = 10.9, 12.8 Hz), 2.45 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 149.7, 143.9, 141.7, 139.6, 138.1, 135.2, 129.4, 128.8, 128.7, 128.5, 127.7, 127.5, 127.0, 126.2, 119.6, 116.7, 101.1, 71.2, 62.0, 50.8, 21.5; HRMS (ESI-TOF) calcd for C30H29N2O2S (M + H)+ 481.1950, found 481.1947. 2-methylene-4-phenyl-1-tosyldecahydroquinoxaline (4m). The general method described above was followed when 1h (50.0 mg, 0.198 mmol, 1.0 equiv) was reacted with 2a (55 μL, 0.596 mmol, 3.0 equiv) followed by reaction with 3a (40.3 mg, 0.258 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (22.9 mg, 0.019 mmol, 0.1 equiv) and (±)-BINAP (24.7 mg, 0.039 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4m (67.7 mg, 0.177 mmol) as a thick liquid in 88% yield. Rf 0.70 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 2927, 2857, 1736, 1597, 1494, 1450, 1324, 1262, 1162, 1089, 894, 814, 750, 700, 665, 573, 551; 1H NMR (500 MHz, CDCl3) δ 7.69 (d, 2H, J = 8.5 Hz), 7.16–7.12 (m, 4H), 6.91 (t, 1H, J = 7.3 Hz), 6.65 (d, 2H, J = 7.3 Hz), 5.35 (d, 1H, J = 1.8 Hz), 4.95 (brs, 1H), 3.70–3.62 (m, 2H), 3.49–3.46 (m, 1H), 2.88–2.84 (m, 1H), 2.48–2.44 (m, 1H), 2.33 (s, 3H), 1.78–1.55 (m, 4H), 1.41–1.12 (m, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 148.5, 143.3,


Page 22 of 32

Page 23 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


139.1, 136.8, 129.2, 128.6, 127.6, 122.2, 122.1, 118.4, 111.3, 64.7, 60.6, 55.9, 33.2, 30.6, 25.1, 24.7, 21.4; HRMS (ESI-TOF) calcd for C22H27N2O2S (M + H)+ 383.1793, found 383.1796. 2-methylene-4-phenyl-1-tosyloctahydro-1H-cyclopenta[b]pyrazine (4n). The general method described above was followed when 1g (50.0 mg, 0.211 mmol, 1.0 equiv) was reacted with 2a (58 μL, 0.632 mmol, 3.0 equiv) followed by reaction with 3a (42.7 mg, 0.274 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (24.3 mg, 0.021 mmol, 0.1 equiv) and (±)-BINAP (26.2 mg, 0.042 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4n (60.0 mg, 0.163 mmol) as a semi-solid in 77% yield. Rf 0.68 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 2923, 2856, 1647, 1598, 1498, 1455, 1354, 1309, 1261, 1203, 1184, 1169, 1128, 1091, 1035, 1004, 991, 959, 899, 815, 756, 707, 697, 668, 654, 580, 550 ; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 2H, J = 7.9 Hz), 7.33 (d, 2H, J = 7.9 Hz), 7.21–7.17 (m, 2H), 6.81 (t, 1H, J = 7.3 Hz), 6.71 (d, 2H, J = 8.5 Hz), 5.41 (s, 1H), 4.82 (s, 1H), 3.53–3.38 (m, 4H), 2.62–2.55 (m, 1H), 2.45 (s, 3H), 2.35–2.27 (m, 1H), 2.00–1.70 (m, 3H), 1.28–1.18 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 150.8, 144.0, 139.4, 134.1, 129.6, 128.8, 127.7, 119.7, 117.4, 111.2, 62.6, 61.6, 57.0, 30.6, 27.8, 21.6, 19.4; HRMS (ESI-TOF) calcd for C21H25N2O2S (M + H)+ 369.1637, found 369.1606. 2-methylene-4-(p-tolyl)-1-tosyldecahydroquinoxaline (4o). The general method described above was followed when 1h (50.0 mg, 0.199 mmol, 1.0 equiv) was reacted with 2c (63 μL, 0.597 mmol, 3.0 equiv) followed by reaction with 3a (40.4 mg, 0.259 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (22.9 mg, 0.019 mmol, 0.1 equiv) and (±)-BINAP (24.7 mg, 0.039 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4o (62.2 mg, 0.157 mmol) as a semi-solid in 79% yield. Rf 0.70 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 2920, 2856, 1740, 1597, 1494, 1452, 1328, 1270, 1163, 1091, 886, 810, 755, 739, 701, 664, 580, 548, 506; 1H NMR (500 MHz, CDCl3) δ 7.74 (d, 2H, J = 8.3 Hz), 7.19 (d, 2H, J = 8.0 Hz), 6.98 (d, 2H, J = 8.0 Hz), 6.63 (d, 2H, J = 8.1 Hz), 5.34



Page 24 of 32

(s, 1H), 4.95 (s, 1H), 3.66–3.58 (m, 2H), 3.45–3.43 (m, 1H), 2.82–2.77 (m, 1H), 2.45–2.42 (m, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 1.75–1.52 (m, 4H), 1.41–1.33 (m, 1H), 1.25–1.18 (m, 1H), 1.09– 1.01 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 146.2, 143.2, 138.9, 136.9, 132.8, 129.7, 129.28, 129.20, 127.7, 123.7, 111.8, 65.2, 60.9, 57.2, 33.2, 30.8, 25.0, 24.7, 21.4, 20.7; HRMS (ESI-TOF) calcd for C23H29N2O2S (M + H)+ 397.1950, found 397.1954. 4-(4-(tert-butyl)phenyl)-2-methylene-1-tosyloctahydro-1H-cyclopenta[b]pyrazine

(4p).

The

general method described above was followed when 1g (50.0 mg, 0.211 mmol, 1.0 equiv) was reacted with 2d (0.1 mL, 0.632 mmol, 3.0 equiv) followed by reaction with 3a (42.7 mg, 0.274 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (24.3 mg, 0.021 mmol, 0.1 equiv) and (±)-BINAP (26.2 mg, 0.042 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4p (64.5 mg, 0.152 mmol) as a semi-solid in 72% yield. Rf 0.70 (EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 2958, 1646, 1609, 1513, 1457, 1358, 1309, 1184, 1169, 1091, 1002, 960, 897, 815, 708, 685, 662, 634, 593, 561, 548; 1H NMR (500 MHz, CDCl3) δ 7.70 (d, 2H, J = 8.3 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.20 (d, 2H, J = 8.7 Hz), 6.66 (d, 2H, J = 8.7 Hz), 5.40 (s, 1H), 4.82 (s, 1H), 3.51–3.38 (m, 4H), 2.60–2.54 (m, 1H), 2.46 (s, 3H), 2.31–2.25 (m, 1H), 1.97–1.90 (m, 1H), 1.85–1.72 (m, 2H), 1.30– 1.20 (m, 10H); 13C{1H} NMR (125 MHz, CDCl3) δ 148.5, 143.9, 142.6, 139.5, 134.3, 129.6, 127.7, 125.6, 117.2, 111.0, 62.6, 62.0, 57.1, 33.9, 31.4, 30.6, 28.0, 21.6, 19.4; HRMS (ESI-TOF) calcd for C25H33N2O2S (M + H)+ 425.2263, found 425.2261. (Z)-2-benzylidene-4-(p-tolyl)-1-tosyldecahydroquinoxaline (4q). The general method described above was followed when 1h (50.0 mg, 0.199 mmol, 1.0 equiv) was reacted with 2c (66 μL, 0.596 mmol, 3.0 equiv) followed by reaction with 3b (60.2 mg, 0.259 mmol, 1.3 equiv) in the presence of Pd(PPh3)4 (22.9 mg, 0.019 mmol, 0.1 equiv) and (±)-BINAP (24.7 mg, 0.039 mmol, 0.2 equiv) in DMSO (2.0 mL) to afford 4q (75.2 mg, 0.160 mmol) as a semi-solid in 80% yield. Rf 0.68


Page 25 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(EtOAc : petroleum ether, 2:8); IR ν̃max (CH2Cl2, cm−1) 3398, 2931, 2857, 1618, 1520, 1490, 1448, 1333, 1258, 1152, 1122, 1090, 1041, 887, 807, 757, 691, 661, 577, 546; 1H NMR (500 MHz, CDCl3) δ 7.85 (d, 2H, J = 8.3 Hz), 7.30–7.22 (m, 5H), 7.11–7.09 (m, 2H), 6.91 (d, 2H, J = 8.1 Hz), 6.40 (d, 2H, J = 8.4 Hz), 4.47–4.44 (m, 1H), 4.03–4.00 (m, 1H), 3.77 (brs, 1H), 3.69–3.64 (m, 1H), 3.34–3.29 (m, 1H), 2.40 (s, 4H), 2.20 (s, 3H), 1.81–1.61 (m, 4H), 1.32–1.20 (m, 2H), 1.15–1.07 (m, 1H);

13C{1H}

NMR (125 MHz, CDCl3) δ 144.8, 143.3, 137.9, 131.3, 129.6, 129.5, 128.1,

128.0, 127.3, 126.0, 122.4, 112.9, 85.1, 84.1, 61.5, 53.7, 33.5, 33.0, 30.9, 25.8, 24.3, 21.4, 20.3; HRMS (ESI-TOF) calcd for C29H33N2O2S (M + H)+ 473.2263, found 473.2265. Author Information Corresponding Author *E-mail: [email protected]. ORCID Manas K. Ghorai: 0000-0002-0472-4757 Navya Chauhan: 0000-0002-4931-2932 Notes The authors declare no competing financial interest. Associated Content Supporting Information



Copies of 1H and

13C{1H}

NMR spectra of the compounds, HPLC chromatograms for ee

determination and details of single crystal X-ray analysis of compound 4a. This material is available free of charge via the Internet at http://pubs.acs.org. Acknowledgment M.K.G. is grateful to IIT Kanpur, India. N.C. thanks UGC, India and S.P. thanks CSIR, India for research fellowships.References (1) (a) Ye, Z.; Adhikari, S.; Xia, Y.; Dai, M. Expedient syntheses of N-heterocycles via intermolecular amphoteric diamination of allenes. Nat. Commun. 2018, 9, 721–731. (b) Feng, Y.; LoGrasso, P. V.; Defert, O.; Li, R. Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential. J. Med. Chem. 2016, 59, 2269–2300. (c) Domling, A.; Wang, W.; Wang, K. Chemistry and Biology Of Multicomponent Reactions. Chem. Rev. 2012, 112, 3083–3135. (2) (a) Chandrika, N. T.; Shrestha, S. K.; Ngo, H. X.; Tsodikov, O. V.; Howard, K. C.; GarneauTsodikova, S. Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents. J. Med. Chem. 2018, 61, 158–173. (b) Liu, H.; Tian, Y.; Lee, K.; Krishnan, P.; Wang, M. K.-M.; Whelan, S.; Mevers, E.; Soloveva, V.; Dedic, B.; Liu, X.; Cunningham, J. M. Identification of Potent Ebola Virus Entry Inhibitors with Suitable Properties for in Vivo Studies. J. Med. Chem. 2018, 61, 6293– 6307. (c) Zhao, Y.; Gu, Q.; Morris-Natschke, S. L.; Chen, C.-H.; Lee, K.-H. Incorporation of Privileged Structures into Bevirimat Can Improve Activity against Wild-Type and BevirimatResistant HIV-1. J. Med. Chem. 2016, 59, 9262–9268. (d) Firth, J. D.; O’Brien, P.; Ferris, L. Synthesis of Enantiopure Piperazines via Asymmetric Lithiation–Trapping of N-Boc Piperazines: Unexpected Role of the Electrophile and Distal N-Substituent. J. Am. Chem. Soc. 2016, 138, 651– 659.


Page 26 of 32

Page 27 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(3) (a) Gu, Z.-S.; Zhou, A.-n.; Xiao, Y.; Zhang, Q.-W.; Li, J.-Q. Synthesis and antidepressant-like activity of novel aralkyl piperazine derivatives targeting SSRI/5-HT1A/5-HT7. Eur. J. Med. Chem. 2018, 144, 701–715. (b) da Silva, D. M.; Sanz, G.; Vaz, B. G.; de Carvalho, F. S.; Liao, L. M.; de Oliveira, D. R.; Moreira, L. K. d. S.; Cardoso, C. S.; de Brito, A. F.; da Silva, D. P. B.; da Rocha, F. F.; Santana, I. G. C.; Galdino, P. M.; Costa, E. A.; Menegatti, R. Tert-butyl 4-((1-phenyl1H-pyrazol-4-yl) methyl) piperazine-1-carboxylate (LQFM104)- New piperazine derivative with antianxiety and antidepressant-like effects: Putative role of serotonergic system. Biomed. Pharmacother. 2018, 103, 546–552. (c) Gupta, S.; Pandey, D.; Mandalapu, D.; Sharma, V.; Shukla, M.; Singh, S.; Singh, N.; Yadav, S. K.; Tanpula, D. K.; Singh, S.; Maikhuri, J. P.; Shukla, S.; Lal, J.; Siddiqi, M. I.; Gupta, G.; Sharma, V. L. Novel aryl piperazines for alleviation of ‘andropause’ associated prostatic disorders and depression. Eur. J. Med. Chem. 2017, 132, 204– 218. (4) Mizojiri, R.; Nakata, D.; Satoh, Y.; Morishita, D.; Shibata, S.; Iwatani-Yoshihara, M.; Kosugi, Y.; Kosaka, M.; Takeda, J.; Sasaki, S.; Takami, K.; Fukuda, K.; Kamaura, M.; Sasaki, S.; Arai, R.; Cary, D. R.; Imaeda, Y. Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1H)-one Derivatives as Orally eIF4A3-Selective Inhibitors. ACS Med. Chem. Lett. 2017, 8, 1077–1082 and references cited therein. (5) (a) Pytka, K.; Gluch-Lutwin, M.; Kotanska, M.; Waszkielewicz, A.; Kij, A.; Walczak, M. Single Administration of HBK-15—a Triple 5-HT1A, 5-HT7, and 5-HT3 Receptor Antagonist—Reverses Depressive-Like Behaviors in Mouse Model of Depression Induced by Corticosterone. Mol. Neurobiol.

2018, 55, 3931–3945. (b) Bang-Andersen; Benny, O.; Kurre, C.; Sanchez, C. The Discovery of the Antidepressant Vortioxetine and the Research that Uncovered Its Potential to Treat the Cognitive Dysfunction Associated with Depression. Successful Drug Discovery 2017, 2, 191–214.



Page 28 of 32

(6) (a) Banu, S.; Bollu, R.; Naseema, M.; Gomedhika, P. M.; Nagarapu, L.; Sirisha, K.; Kumar, C. G.; Gundasw, S. K. A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis, anti-microbial evaluation and molecular docking studies. Bioorg. Med. Chem. Lett. 2018, 28, 1166–1170. (b) Chen, Y.-Y.; Gopala, L.; Bheemanaboina, R. R. Y.; Liu, H.-B.; Cheng, Y.; Geng, R.-X.; Zhou, C.-H. Novel Naphthalimide Aminothiazoles as Potential Multitargeting Antimicrobial Agents. ACS Med. Chem. Lett. 2017, 8, 1331–1335. (7) (a) Periasamy, M.; Reddy, P. O.; Edukondalu, A.; Dalai, M.; Alakonda, L. M.; Udaykumar, B. Zinc Salt Promoted Diastereoselective Synthesis of Chiral Propargylamines Using Chiral Piperazines and Their Enantioselective Conversion into Chiral Allenes. Eur. J. Org. Chem. 2014, 6067–6076. (b) Li, P.; Chai, Z.; Zhao, S.-L.; Yang, Y.-Q.; Wang, H.-F.; Zheng, C.-W.; Cai, Y.-P.; Zhao,

G.;

Zhu,

S.-Z.

Highly enantio-

and

diastereoselective

synthesis

of

α-

trifluoromethyldihydropyrans using a novel bifunctional piperazine-thiourea catalyst. Chem. Commun. 2009, 47, 7369–7371. (c) Wang, Z.; Cheng, M.; Wu, P.; Wei, S.; Sun, J. L-Piperazine2-carboxylic Acid Derived N-Formamide as a Highly Enantioselective Lewis Basic Catalyst for Hydrosilylation of N-Aryl Imines with an Unprecedented Substrate Profile. Org. Lett. 2006, 8, 3045–3048. (d) Mitchell, C. E.; Brenner, S. E.; Ley, S. V. A versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones. Chem. Commun. 2005, 42, 5346–5348. (e) Hanessian, S.; Pham, V. Catalytic Asymmetric Conjugate Addition of Nitroalkanes to Cycloalkenones. Org. Lett. 2000, 2, 2975–2978. (8) (a) Zhang, R.; Ni1, C.; He, Z; Hu, J. Organocatalyzed Decarboxylative Trifluoromethylation of βKetoacids. Top. Catal. 2018, 61, 664–673. (b) Rodrigo, E.; Alcubilla, B. G.; Sainz, R.; Fierro, J. L.

G.; Ferritto, R.; Cid, M. B. Reduced graphene oxide supported piperazine in aminocatalysis. Chem. Commun. 2014, 50, 6270–6273. (c) Pérez-Sánchez, M.; de María, P. D. Synthesis of


Page 29 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


natural fragrance jasminaldehyde using silica-immobilized piperazine as organocatalyst. Catal. Sci. Technol. 2013, 3, 2732–2736. (d) Barros, M. T.; Phillips, A. M. F. Chiral Piperazines as Efficient Catalysts for the Asymmetric Michael Addition of Aldehydes to Nitroalkenes. Eur. J. Org. Chem. 2007, 178–185. (e) Nakamura, D.; Kakiuchi, K.; Koga, K.; Shirai, R. Design and Synthesis of Novel C2-Symmetric Chiral Piperazines and an Application to Asymmetric Acylation of σ-Symmetric 1,2-Diols. Org. Lett. 2006, 8, 6139–6142. (9) (a) Ibeanu, F. N.; Onoabedje, E. A.; Ibezim, A.; Okoro, U. C. Synthesis, characterization, computational and biological study of novel azabenzo[a]phenothiazine and azabenzo[b]phenoxazine heterocycles as potential antibiotic agent. Med. Chem. Res. 2018, 27, 1093–1102. (b) Soudani, S.;

Jeanneau, E.; Jelsch, C.; Lefebvre, F.; Nasr, C. B. Structural, crystal structure, Hirshfeld surface analysis and physicochemical studies of a new chlorocadmate template by 1-(2hydroxyethyl)piperazine. J. Mol. Struct. 2016, 1123, 66–74. (c) Hawes, C. S.; Hamilton, S. E.; Hicks, J.; Knowles, G. P.; Chaffee, A. L.; Turner, D. R.; Batten, S. R. Coordination Chemistry and Structural Dynamics of a Long and Flexible Piperazine-Derived Ligand. Inorg. Chem. 2016, 55, 6692–6702. (d) Wang, X.; Mu, B.; Lin, H.; Liu, G.; Tian, A.; Yang, S. Assembly and property of four 2D layer-like coordination polymers with different structural features derived from bis(3pyridylformyl)piperazine ligand and

aromatic

dicarboxylic

acids with nitro group.

CrystEngComm 2012, 14, 1001–1009. (10) (a) Borlinghaus, N.; Gergel, S.; Nestl, B. M. Biocatalytic Access to Piperazines from Diamines and Dicarbonyls. ACS Catalysis 2018, 8, 3727–3732. (b) Jindakun, C.; Hsieh, S. Y.; Bode, J. W. Iridium-catalyzed Synthesis of Saturated N-Heterocycles from Aldehydes and SnAP Reagents with Continuous Flow Photochemistry. Org. Lett. 2018, 20, 2071–2075. (c) Chamakuri, S.; Jain, P.; Guduru, S. K. R.; Arney, J. W.; MacKenzie, K. R.; Santini, C.; Young, D. W. Synthesis



of Enantiomerically Pure 6-Substituted-Piperazine-2-Acetic Acid Esters as Intermediates for Library Production. J. Org. Chem. 2018, 83, 6541–6555. (d) Usmanova, L.; Dar'in, D.; Novikov, M. S.; Gureev, M.; Krasavin, M. Bicyclic Piperazine Mimetics of the Peptide β-Turn Assembled via the Castagnoli–Cushman Reaction. J. Org. Chem. 2018, 83, 5859–5868. (e) Periasamy, M.; Edukondalu, A.; Reddy, P. O. Synthesis of Chiral 2,3-Disubstituted 1,4-Diazabicyclo[2.2.2]octane Derivatives. J. Org. Chem. 2015, 80, 3651–3655. (f) Montgomery, T. D.; Rawal, V. H. PalladiumCatalyzed Modular Synthesis of Substituted Piperazines and Related Nitrogen Heterocycles. Org. Lett. 2016, 18, 740–743. (g) Lau, Y. Y.; Zhai, H.; Schafer, L. L. Catalytic Asymmetric Synthesis of Morpholines. Using Mechanistic Insights to Realize the Enantioselective Synthesis of Piperazines. J. Org. Chem. 2016, 81, 8696–8709. (h) Crestey, F.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. Expedite Protocol for Construction of Chiral Regioselectively N-Protected Monosubstituted Piperazine, 1,4-Diazepane, and 1,4-Diazocane Building Blocks. J. Org. Chem. 2009, 74, 5652–5655. (i) Olsen, C. A.; Christensen, C.; Nielsen, B.; Farah, M. M.; Witt, M.; Clausen, R. P.; Kristensen, J. L.; Franzyk, H.; Jaroszewski, J. W. Aminolysis of Resin-Bound NNosylaziridine-2-carboxylic Acids. Org. Lett., 2006, 8, 3371–3374. (11) (a) Ghorai, M. K.; Bhattacharyya, A.; Das, S.; Chauhan, N. Ring Expansions of Activated Aziridines and Azetidines. Top. Heterocycl. Chem. 2016, 41, 49–142. (b) Dolfen, J.; De Kimpe, N.; D’hooghe, M. Deployment of Small-Ring Azaheterocycles as Building Blocks for the Synthesis of Organofluorine Compounds. Synlett 2016, 27, 1486–1510. (c) Dolfen, J.; Vervisch, K.; DeKimpe, N.; D’hooghe, M. LiAlH4‐Induced Selective Ring Rearrangement of 2‐(2‐Cyanoethyl)aziridines toward 2‐(Aminomethyl)pyrrolidines and 3‐Aminopiperidines as Eligible Heterocyclic Building Blocks. Chem. Eur. J. 2016, 22, 4945–4951. (d) Callebaut, G.; Meiresonne, T.; De Kimpe, N.; Mangelinckx, S. Synthesis and Reactivity of 2-


Page 30 of 32

Page 31 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(Carboxymethyl)aziridine Derivatives. Chem. Rev. 2014, 114, 7954–8015. (e) Schneider, C. Catalytic, Enantioselective Ring Opening of Aziridines. Angew. Chem., Int. Ed. 2009, 48, 2082– 2084. (f) Stankovic, S.; D’hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.; Speybroeck, V. V.; De Kimpe, N.; Ha, H. J. Regioselectivity in the ring opening of non-activated aziridines. Chem. Soc. Rev. 2012, 41, 643–665 and refernces cited therein. (12) (a) Pradhan, S.; Shahi, C. K.; Bhattacharyya, A.; Ghorai, M. K. Stereoselective synthesis of 3-spiropiperidino indolenines via SN2-type ring opening of activated aziridines with 1Hindoles/Pd-catalyzed spirocyclization with propargyl carbonates. Chem. Commun. 2018, 54, 8583–8586. (b) Mal, A.; Goswami, G.; Wani, I. A.; Ghorai, M. K. Synthetic route to chiral indolines via Cu(OAc)2-catalyzed ring-opening/C(sp2)–H activation of activated aziridines. Chem. Commun. 2017, 53, 10263–10266. (c) Bhattacharyya, A.; Shahi, C. K.; Pradhan, S.; Ghorai, M. K. Stereospecific Synthesis of 1,4,5,6-Tetrahydropyrimidines via Domino Ring-Opening Cyclization of Activated Aziridines with α-Acidic Isocyanides. Org. Lett. 2018, 20, 2925–2928. (d) Wani, I. A.; Sayyad, M.; Ghorai, M. K. Domino ring-opening cyclization (DROC) of activated aziridines and epoxides with nitronesvia dual-catalysis “on water”. Chem. Commun. 2017, 53, 4386–4389. (e) Shahi, C. K.; Bhattacharyya, A.; Nanaji, Y.; Ghorai, M. K. A Stereoselective Route to Tetrahydrobenzoxazepines and Tetrahydrobenzodiazepines via Ring-Opening and Aza-Michael Addition of Activated Aziridines with 2-Hydroxyphenyl and 2-Aminophenyl Acrylates. J. Org. Chem. 2017, 82, 37–47. (f) Pradhan, S.; Shahi, C. K.; Bhattacharyya, A.; Chauhan, N.; Ghorai, M. K. Syntheses of Tetrahydrobenzoazepinoindoles and Dihydrobenzodiazepinoindoles via RingOpening Cyclization of Activated Aziridines with 2-(2-Bromophenyl)-1H-indoles. Org. Lett. 2017, 19, 3438–3441. (g) Mal, A.; Sayyad, M.; Wani, I. A.; Ghorai, M. K. Domino Ring-Opening Cyclization of Activated Aziridines with Indoles: Synthesis of Chiral Hexahydropyrroloindoles.



Page 32 of 32

J. Org. Chem. 2017, 82, 4–11. (h) Ghorai, M. K.; Shahi, C. K.; Bhattacharyya, A.; Sayyad, M.; Mal, A.; Wani, I. A.; Chauhan, N. Syntheses of Tetrahydrobenzodiazepines via SN2‐Type Ring‐Opening

of

Activated

Aziridines

with

2‐Bromobenzylamine

Followed

by

Copper‐Powder‐Mediated C−N Bond Formation. Asian. J. Org. Chem. 2015, 4, 1103–1111. (13) During the preparation of this manuscript, Punniyamurthy et. al. reported Cu-catalyzed ringopening of aziridines with propargyl amines followed by hydroamination to form piperazines which further isomerize to tetrahydropyrazines. Das, B. K.; Pradhan, S.; Punniyamurthy, T. Stereospecific Ring Opening and Cycloisomerization of

Aziridines

with

Propargylamines:

Synthesis

of

Functionalized

Piperazines

and

Tetrahydropyrazines. Org. Lett. 2018, 20, 4444–4448. (14) See the supporting information for details. (15) Armarego, W. L. F.; Chai, C. Purification of Laboratory Chemicals; Butterworth-Heinemann: Oxford, 2012. (16) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B. Bromine-Catalyzed Aziridination of Olefins. A Rare Example of Atom-Transfer Redox Catalysis by a Main Group Element. J. Am. Chem. Soc. 1998, 120, 6844–6845. (17) Cernerud, M.; Adolfsson, H.; Moberg, C. C3-symmetric tripodal tetra-amines—preparation from chiral amino alcohols via aziridines. Tetrahedron: Asymmetry 1997, 8, 2655–2662. (18) Zhou, Z.; Liu, G.; Chen, Y.; Lu, X. Cascade Synthesis of 3-Alkylidene Dihydrobenzofuran Derivatives via Rhodium(III)-Catalyzed Redox-Neutral C–H Functionalization/Cyclization Org. Lett. 2015, 17, 5874–5877.


Stereospecific Synthesis of Highly Substituted Piperazines via an One

Recommend Documents