N-Heterocyclic Carbene catalyzed one-pot sequential alpha arylation

Subscriber access provided by Kaohsiung Medical University

Article

Palladium(II)/N-Heterocyclic Carbene catalyzed one-pot sequential alpha arylation/alkylation: Access to 3,3-disubstituted oxindoles Pradeep Kumar Reddy Panyam, Bharat Ugale, and Thirumanavelan Gandhi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00264 • Publication Date (Web): 08 Jun 2018 Downloaded from http://pubs.acs.org on June 8, 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 38 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

Palladium(II)/N-Heterocyclic sequential

alpha

Carbene

arylation/alkylation:

catalyzed Access

one-pot to

3,3-

disubstituted oxindoles Pradeep Kumar Reddy Panyam,§ Bharat Ugale,† and Thirumanavelan Gandhi,*,§ §

†

Department of Chemistry, School of Advanced Sciences, VIT University, Vellore 632014, India

Department of Chemistry, Indian Institute of Technology Ropar, Punjab 140001, India E-mail: [email protected]

ABSTRACT Rationally designed fluorene-based mono- and bimetallic Pd-PEPPSI complexes were synthesized and demonstrated to be effective for the one-pot sequential αarylation/alkylation of oxindoles. This streamlined approach offers efficient access to functionalized 3,3-disubstituted oxindoles in excellent yields (up to 89%) under mild reaction conditions. INTRODUCTION Oxindoles are privileged structural motif prevalent in natural products, pharmaceuticals, agrochemicals, and bioactive compounds (Figure 1).1 Of these, 3,31 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 38

disubstituted oxindoles have attracted much interest from synthetic chemists in light of its challenging tertiary carbon at C-3 and complementary bioactivity manifestation. Although plethora of reports on the chemistries of spiroindoles has been published,2 studies on 3-alkyl-3-aryloxindoles are limited.

Figure 1. Biologically relevant molecules with 3,3-disubstituted oxindoles.

Traditionally,

3,3-disubstituted

oxindoles

were

synthesized

by

double

electrophilic aromatic substitution of isatin involving strong acids via 3-hydroxyl-3aryloxindoles.3 Additionally, isatin undergoes nucleophilic addition4 to form desired products in the presence of transition metal catalysts. Pioneering studies by Miura,5 Buchwald,6 and Hartwig7 on α-arylation started off intramolecular α-arylation of amides,8 and later applied to the synthesis of oxindoles.6c, 6d,

9

Furthermore, careful selection of

cyclization precursors leads to an access to 3,3-disubstituted oxindoles either by direct oxidative α-arylation of amides10 or upon intramolecular Heck reactions.8c,

11

3,3-

disubstituted oxindoles were also generated by simple direct functionalization of 3substituted oxindoles.12 Thus far, great progress has been witnessed in synthesizing 3,3disubstituted oxindoles.13 Notwithstanding, most of these approaches rely on prefunctionalized amides, multistep synthesis and harsh reaction conditions (pyrophoric

2 ACS Paragon Plus Environment

Page 3 of 38 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


bases, expensive ligands and fewer diversifications), demands definite improvement in the synthesis of 3,3-disubstituted oxindoles. Over the past decade, NHCs emerged as an up-and-coming ancillary ligand, and its versatility and suitability in homogenous catalysis have been well realised.

Its

popularity in catalysis is substantiated as it forms stable complexes with transition metal salts and participates in various catalytic organic transformations. Strong σ-donating and weaker π-accepting abilities of NHCs make them unique and robust and outsmart the phosphine ligands.14 Recently, we have reported the straightforward, convenient, and one-pot synthesis of 2-alkenylindoles catalyzed by Pd-NHCs (appended with naphthalimide or bisnaphthalimide) from o-haloanilines and tertiary propargyl alcohols.15 This appealing report inspired us to design and develop new Pd-NHCs catalysts. Herein, we report an unambiguous and one-pot synthesis of 3-alkyl-3-aryloxindoles catalyzed by newly synthesized fluorene-based Pd-NHC complexes. In addition, this protocol proceeds with excellent substrate scope and yields under moderate reaction conditions. RESULTS AND DISCUSSION The ligand systems were synthesized by copper mediated N-arylation of imidazoles by 2-bromo-9,9-dibutyl-9H-fluorene 1 followed by reacting with various alkyl bromides to give corresponding azolium salts 3a-3c. Likewise, 7a-7c were synthesized by choosing 2,7-dibromo-9,9-dibutyl-9H-fluorene 5 as the arylating partner (Scheme 1).



Imidazole(1.1 equiv) Cu2O (5 mol %) Dipivaloylmethane (10 mol %) Cs2CO3 (2 equiv)

Page 4 of 38

RX (3 equiv) Acetonitrile 80 °C, 24 h

DMSO. 120 °C, 12 h

N

N

Br 1

N

N

R

2; 81%

X X = Br 3a; 92% R = Et Br 3b; 95% n-Bu Br 3c; 87% Benzyl R X N

N Br

Imidazole (2.2 equiv) Cu2O (10 mol %) Dipivaloylmethane (20 mol %) Cs2CO3 (4 equiv)

N

N

RX (6 equiv) Acetonitrile 80 °C, 36 h

DMSO. 120 °C, 12 h

Br

N

N N

5

N R X

6; 72%

X = Br 7a; 89% R = Et Br 7b; 93% n-Bu Benzyl Br 7c; 90%

Scheme 1. Synthesis of fluorene based mono and bisimidazolium salts. Treatment of the azolium salt 3a-3c, at 80 °C, with 1.05 equiv of PdCl2, 5 equiv of K2CO3, 3 equiv of KBr in pyridine (5 mL) for 16 h resulted in PEPPSI (PyridineEnhanced Precatalyst Preparation Stabilization

and Initiation)

type

trans-

(NHC)PdBr2(py) complexes 4a-4c (Yield range 71-73%). Complexes 8a-8c (Yield range 52-61%) were prepared by adapting the aforementioned procedure by doubling the stoichiometric quantities of PdCl2 (2.1 equiv), K2CO3 (10 equiv) & KBr (6 equiv) to 7a7c (Scheme 2). The crude complexes were purified over a short-pad of silica and they were isolated as yellow solids. These yellow solids were freely soluble in DCM and CH3CN and air-stable. The synthesized complexes 4a-4c & 8a-8c were identified by 4 ACS Paragon Plus Environment

Page 5 of 38 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


multinuclear NMR and ESI-MS. The absence of imidazolium NC(H)N proton resonances and the presence of pyridine proton resonances in the 1H NMR spectra of 4a-4c & 8a-8c exemplifies that the imidazolium moieties were deprotonated and coordinated to Pd with pyridine as an ancillary ligand. Pd-C carbene signals appear within a range of δ 148.21 to 149.87 in the 13C NMR spectrum.

Scheme 2. Synthesis of mono- and bis-palladium-PEPPSI complexes. The molecular structure of monometallic 4c and bimetallic 8a were unequivocally established by single crystal X-ray analysis.16 Pale yellow coloured crystals of 4c and 8a were grown by slow evaporation of saturated dichloromethane solution at ambient conditions. Comparatively, both 4c and 8a exhibit square-planar geometry around the palladium metal center with the carbene and pyridine oriented trans to one another. ORTEP representations at 50% probability for 4c and 8a are shown in the Figure 2. The



Page 6 of 38

Pd-C carbene bond length in 4c is 1.963(3) Å and the Pd-C carbene bond lengths in 8a for Pd1 and Pd2 are 1.968(5) Å, which are quite analogous to those of structurally related complexes.15

Figure 2. Crystal structures of Pd-NHC complexes 4c and 8a. (Thermal ellipsoids are shown at 50% probability level) The applicability of Pd salts in the synthesis of 3,3-disubstituted oxindoles has been extensively studied. However, it incurred with downside involving expensive phosphine ligands and employment of strong bases. To circumvent this hurdle, we utilized the synthesized Pd-NHCs 4a-4c and 8a-8c to synthesize 3-alkyl-3-aryloxindoles. We commenced our investigations on the α-arylation of N-methyl oxindole 1a using bromobenzene 2a as a coupling partner, 4a as a catalyst and KOt-Bu as a base in toluene at 80 °C for 6 h. Subsequently, the addition of n-butyl bromide to the reaction mixture and stirring for 2 h resulted in 3-butyl-3-phenyloxindoles 3aa in 54% yield (Table 1, entry 1). Switching the solvent from toluene to THF displayed enhancement in the yield of 3aa to 76% (entry 5). Screening of various bases was found to be ineffective (entry 6 12). Bases such as K2CO3, Cs2CO3, triethylamine, DBU and sodium acetate (entry 6-7 & 10-12) were not successful indicating the importance of metal enolate formation as 6 ACS Paragon Plus Environment

Page 7 of 38 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


reported earlier by Willis and coworkers. However, strong bases such as NaOH and KOH in combination with our Pd-NHC delivered only trace amounts of 3aa. Table 1. Optimization of the catalyst system.[a,b]

Entry

[Pd]

Base

Solvent

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4b 4c 8a 8b 8c 8c Pd(OAc)2/PPh3 Pd(OAc)2/1,10phenathroline Pd(PPh3)2Cl2 Pd(PPh3)4 5%- Pd/C 10%- Pd/C

KOt-Bu KOt-Bu KOt-Bu KOt-Bu KOt-Bu K2CO3 Cs2CO3 KOH NaOH Triethylamine DBU Sodium acetate KOt-Bu KOt-Bu KOt-Bu KOt-Bu KOt-Bu KOt-Bu[f] KOt-Bu KOt-Bu

Toluene DMSO NMP 1,4-dioxane THF THF THF THF THF THF THF THF THF THF THF THF THF THF THF THF

Yields (%) 3aa 54 27 57 71 [c] 76 , 59[d] 21 36 16 11 23

N-Heterocyclic Carbene catalyzed one-pot sequential alpha arylation

Recommend Documents