Fabrication and Diverse Ring-Expansion Nanocatalysis of

Subscriber access provided by University of Groningen

Article

Fabrication and Diverse Ring-Expansion Nanocatalysis of Functionalized Pt-Nanoparticles to a General Synthesis of Pyrrolines: A 3D-Mid-IR Study Subhadeep Ghosh, Sudipto Debnath, Uttam Kumar Das, and Dilip K. Maiti Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.7b02441 • Publication Date (Web): 04 Oct 2017 Downloaded from http://pubs.acs.org on October 4, 2017

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 free 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 accessible to all readers and 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.

Industrial & Engineering Chemistry Research 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 23

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

Industrial & Engineering Chemistry Research

Fabrication and Diverse Ring-Expansion Nanocatalysis of Functionalized Pt-Nanoparticles to a General Synthesis of Pyrrolines: A 3D-Mid-IR Study Subhadeep Ghosh,¶ Sudipto Debnath, ¶ Uttam K. Das,‡ and Dilip K. Maiti*¶ ¶

Department of Chemistry, University of Calcutta, 92 A. P. C. Road, Kolkata-700009, India; e-mail: [email protected]

‡

Department of Chemistry, School of Physical and Material Sciences, Mahatma Gandhi Central University,

East Champaran, Motihari, Bihar-845401, India

1

ACS Paragon Plus Environment


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 23

ABSTRACT: An unprecedented nanofabrication of functionalised Pt-NPs under mild conditions was accomplished through oxidative insertion of PtBr2 into the O-C bond of ArCH(OMe)2. TEM and SEM imaging, EELS, IV XPS and ESI-MS analyses found the NPs possessing the molecular formula Br2(MeO)Pt CH(OMe)Ph and low dimensional spherical morphology. Ketone and amide functionality-bearing electrophilic cyclopropanes were underwent ring-opening cyclisation. Size dependent catalytic activity of the NPs was investigated using stabilizers and newly introduced PhCH(OMe)2 during synthesis of 2-pyrrolines. The organometallic-NPs were effective for cyclopropane ring-expansion using propargyl amine to 1-pyrrolines with depropargylation. Interestingly the diverse catalytic activity of the Pt-NPs was effective for sp3C-H activated dual cyclization for the direct synthesis of fused-pyrrolo[3,2-c]pyridones. The possible reaction pathway was investigated by 3D-Mid-IR-ATR, control experiments, and ESI-MS analyses. The NPs were superior in terms of simple preparation, low catalyst loading, ease recovery, recycling, diverse catalytic activity and outstanding ability for general synthesis of pyrroline analogues. KEYWORDS: Nanofabrication, oxidative insertion, organometallic NPs, nanocatalysis, ring expansion, pyrrolines

2


Page 3 of 23

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


INTRODUCTION 1 Catalysis is the powerful tool for synthesis of most of the essential chemicals of our modern life and is now 2 moved to heterogeneous catalysis both in industry and academia using metal nanoparticles (NPs) because of 3 their unique catalytic activity, easy recovery and outstanding catalytic turnover. Performance of nanocatalysis relies on their size, shape, composition and innovative chemical property and selectivity. NPs provide an industri4 ally viable finely dispersed heterogeneous reaction media. The catalytic efficiency of NPs may be greatly enhanced by the presence of exchangeable surface ligands on the NPs, which would make it easy to bind substrates and intermediates with metals to deliver the desired product(s) with outstanding efficiency and selectivity. 5 Thus, the discovery of higher oxidation state functionalized metal-NPs is desirable for their potential catalytic activity. The activity could involve the exchange of highly active surface ligands for valuable heterocycles and in6 volve C-C/C-X breaking and coupling to ring expansions. Fabrication of NPs is frequently performed under heating conditions, and achieving functionalized high-valent metal-NPs is difficult because of the tendency of high reactivity of NPs towards decomposition at elevated temperatures. We envisaged overcoming this problem by 7 carrying out a new nanofabrication method involving the oxidative insertion of metals into a suitable bond like CIV O of a readily available organic compound under mild conditions. Pt -based bulk-materials have demonstrated 8 9 anticancer activities, and those are efficient catalysts in hydroamination, cyclisation and Rautenstrauch reac10 IV tions. To the best of our knowledge, the fabrication of Pt -organometallic nanomaterials and development of their catalytic activity are unknown in the literature. Herein, we report on the fabrication of functionalized, highIV valent, Pt -organometallic NPs through oxidative insertion of procatalyst PtBr2 into the C-O bond of ArCH(OMe)2 under mild conditions, and we developed an innovative nanocatalysis process for a diverse cyclopropane ring expansion strategy that can be applied to an unique general synthesis of valuable pyrrolines. The possible reaction pathway of the newly developed catalytic process was thoroughly investigated utilizing in house timeresolved ATR (attenuated total reflectance)-Mid-IR spectroscopy (React-IR), and the recorded 3D-reaction surface monitored at selected point of time of the ongoing reaction, along with ESI-MS study and controlled experiments, which provided useful information of the reaction insight.

Figure 1. Substituted Pyrrolines as Core Scaffold of Pharmaceutically Important Agents Pyrrolines and their analogues are building blocks of bioactive natural alkaloids, biosynthetic intermediates, diabetic drugs, snake-venoms, pharmaceuticals, agrochemicals, pesticides, innovative materials, fluorophore 11-18 dyes, synthons and roasted-smelling odorants in foods. For instance, 1-pyrolline-based natural product lanopylin B1 (A, Fig. 1) and analogues showed broad spectrum of inhibiting human lanosterol synthase and used for treatment of hypercholesterolemia. Another natural product 2-acetyl-1-pyrroline (B, 2-AP) and analogues are important roasted-smelling odorants used in flavor addition industries such as adding delicious popcorn-like aroma

3



Page 4 of 23

11a,12

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

in bread and other cereal products. Functionalized 2-pyrroline (C) was found as antiproliferative agent for 13 human cancer cell. Recently fused-pyrroline bacterioclorin analogue (D) is developed as a dual function agent 14 for fluorescence imaging guided surgery and phototherapy of tumor and cancer. The widespread use of pyrrolines led to the development of several interesting synthetic approaches, such as 2 15 inter- and intramolecular annulation catalysis of imines or amines to ∆ -pyrrolines, and 1,3-dipolar cycloaddition, 1 16 metal catalyzed cyclisation, noncatalytic, multistep methods to ∆ -pyrrolines and tandem cyclisation and cy2 17,18c cloaddition to fused-∆ -pyrrolines. Recently the cyclopropane ring expansion strategies have grown the inter18 est of chemists of academia and industry for synthesis of small and complex molecules. Cyclopropane ringexpansion reactions were also reported for syntheses of pyrrolines, such as photochemical rearrangement of Ncyclopropylimine, formal cycloaddition with nitriles, nucleophilic annulation with amines and domino cyclization of 19 designed cyclopropane precursors. The harsh reaction conditions, use of equivalent amounts of reagents, multiple synthetic steps, using transesterification-prone refluxing alcohol as a solvent and limited substrate scope are the major disadvantages of the reported methods. Moreover, a general catalytic synthesis for highly functionalized pyrroline analogues is unknown in the literature, which is desirable for direct access to diverse classes of pyrrolines. RESULTS AND DISCUSSION We began our experiments on the activation and oxidative insertion of PtBr2 (0.02 mmol) to the C-O bond of 20 PhCH(OMe)2 (0.03 mmol) to fabricate Ph(OMe)HCPtOMe organometallic-NPs using the stabilizer CTAB in toluene (Path a, Scheme 1). We fabricated well-defined, spherical particles 138-149 nm in diameter by a spin coating method (SEM image, Fig. 2a). Our multiple attempts to fabricate smaller NPs of significantly improved catalytic activity using the anionic sodium dodecylsulfonate (SDS) and neutral Tween 20 surfactants were unsuccessful. Gratifyingly fabrication of the smaller organometallic-NPs was observed (Path b, Scheme 1) by replacing CTAB with excess quantity of PhCH(OMe)2 (0.7 mmol). PtBr2 (0.02 mmol) and an excess amount of PhCH(OMe)2 (3a, 1mmol) produced the desired small NPs of dimension about 3nm within 1h in toluene at ambient temperature. PhCH(OMe)2 with two OMe groups and aromatic moieties also acts as an active stabiliser for construction of created nanospace for the fabrication of organometallic-NPs through oxidative insertion. Herein active catalyst is the small spherical NPs, which was confirmed from the dynamic light scattering (DLS) study (3 nm) of the reaction mixture (Fig. 2b) and also FEG-SEM imaging (Fig. 2c) of the fabricated nanomaterials (drop cast method). The presence of the constituting elements, Pt, C, O, Br and H, was confirmed through energy dispersive X-ray spec21 22 troscopy (EDS, Fig. 2d) as well as electron energy-loss spectroscopy (EELS) technology (Supporting Information). ESI-MS analysis of the nanomaterials showed the appearance of a major symbolic peak at 507.8825, which confirmed the formula of the material, [C9H12Br2O2Pt]n. The oxidation state of platinum was investigated 23 using the XPS technique (Fig. 3). The photoelectron line positions are close to those reported by Moulder et al. (Fig. 3a). The scan from 64 to 84 eV for the same sample resulted in a spectrum possessing a symbolic peak at IV ~73.8 eV to Pt 4f5/2, indicating the exclusive presence of the Pt ion (Fig. 2b). The peak at 335.6 eV was ascribed to the acetal carbon bonded with two methoxy groups (Fig. 3c).

Scheme 1. Development of Fabrication Strategy IV After successful fabrication and characterisation of the Pt -organometallic NPs, we investigated their potential catalytic activity for developing a general synthesis approach for valuable pyrroline analogues such as 2pyrrolines, 1-pyrrolines and fused-pyrrolines. Construction of 2-pyrroline (4a) was investigated using easily preIV pared dual-functionalised cyclopropane (1a) and aniline (2a) with in situ generated Pt -NPs (1 mol%) through a

4


Page 5 of 23

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


Figure 2. Characteristic data NPs. (a) SEM image of the Pt-NPs fabricated with stabilizer CTAB (spin coating). (b) DLS data of the NPs achieved with stabilizer PhCH(OMe)2. (c) SEM image of the small NPs. (d) EDS spectrum of the elements present in the NPs. sequential ring opening and tandem ring expanded cyclization (Table 1). A survey of the ring expansion catalysis was studied at room temperature, and it was unsuccessful (entry 1, Table 1). However, the reaction was successful under refluxing conditions to afford compound 4a in a 52% yield (entry 2). The yield (78%) and reaction time (8 h) were significantly improved upon increasing the nanocatalyst loading to 2 mol% (entry 3). The results were not encouraging upon a further increase of the catalyst loading (3 mol%, entry 4). The yield was reduced when CTAB (entry 5) was used because relatively larger organometallic-NPs (dimensions 138-149 nm) were generated under the reaction conditions. The reaction did not occur in the absence of nanocatalysts or the catalyst originator

5



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 6 of 23

IV

Figure 3. XPS data of the Pt -organometallic NPs. (a) Photoelectron line position of the material and (b,c) binding energy curves. benzaldehyde dimethylacetal (3a, entries 6,7). The yields were comparable for the use of 4-methoxy (3b) or 4hydroxymethyl (3c) derivatives (entries 8,9) of benzaldehyde dimethylacetal (3a). The results were discouraging when a more polar, aprotic solvent, such as acetonitrile, tetrahydrofuran (THF) and dioxane (entries 10-12), was used. Herein, 2 mol% of the PhCH(OMe)2 was utilised for oxidative insertion of PtBr2 to achieve NPs for nanocatalysis, and the rest of 3a was utilised as a stabiliser for the fabrication of NPs and as a scavenger for the in situ generated water from the ring expansion reaction, transforming it into PhCHO.

Table 1. Survey of cyclopropane ring expansion catalysis

Entry 1 2 3 4 5 6 7 8 9 10 11 12

PtIV-NPs (mol %) 1 1 2 3 2 0 2 2 2 2 2 2

Solvent (10 mL) toluene toluene toluene toluene toluene toluene toluene toluene toluene THF acetonitrile dioxane

Time (h) 24 18 8 6 18 24 16 18 24 24 24 24

Reaction b conditions c AT reflux reflux reflux refluxd reflux refluxe refluxf g reflux reflux reflux reflux

Yielda (%) 0 52 78 79 64 0 46 76 74 traces 22 39

a

4a found after column chromatography purification, b3a: PhCH(OMe)2 (1mmol); cAT: ambient temperature, dUsing CTAB as a stabilizer, e3a: nil, f 3b: 4-CH3O-C6H4-CH(OMe)2 (1mmol), g3c: 4-CH2OH-C6H4-CH(OMe)2 (1mmol). Under the optimised conditions (entry 3, Table 1), we investigated the scope of this new domino reaction using doubly functionalised cyclopropanes (1) and aromatic/aliphatic amines (2, Scheme 2). As shown in Scheme 2, carbonylarylaminoformyl cyclopropane substrates (1) bearing electron-withdrawing groups (EWG) and electron2 donating groups (EDG) on the phenyl ring (R -groups) reacted smoothly with amines (2a-e) bearing EWG or EDG on their phenyl ring to afford the corresponding 1,2,3-trisubstituted 2-pyrrolines (4a-g) in moderate to high yield

6


Page 7 of 23

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


(68-78%). The doubly activated cyclopropanes bearing an inherent energy strain of approximately 27.5 kcal/mol 24 and a stronger electrophilic nature act as 1,3-dipolar synthons for ring opening, leading to direct construction of pyrrolines.

Scheme 2. Synthesis of Functionalized 2-Pyrrolines (4) IV

Our preliminary investigation on the mechanism of the ring-expansion process tuned by the new Pt organometallic nanocatalyst confirms the presence of benzaldehyde (separated by column chromatography) in the post reaction mixture along with product 4a (entry 1, Scheme 2). Mid-fourier transform infrared (Mid-FTIR) spectroscopy with attenuated total reflection (ATR) is an important technology for gathering fundamental information of an ongoing reaction related to initiation, conversion, intermediate formation, endpoint and reaction 25 rate. Continuous measurements by Mid-IR-ATR provides real-time monitoring of key reaction species. Thus we envisaged that the 3D-reaction surface of this new nanocatalysis process would enable to provide comprehensive evidence for understanding the mechanism. In our 3D Mid-IR-ATR spectral analyses (Fig. 4) of the ongoing reaction among 1-benzoyl-N-phenylcyclopropanecarboxamide (1a), 4-methyl aniline (2a) and benzaldehyde dime-1 thylacetal (3a), we found two symbolic peaks at 1604 and 1674 cm for 1-benzoyl-N-1 phenylcyclopropanecarboxamide (1a, green line, Fig. 5a). As expected, the peak at 1674 cm was vanished after -1 1 h 20 min. A new peak at 1633 cm started to develop after 4 h 30 min, which was corresponding to the desired product (pink line, Fig. 5b). Based on these observations and ESI-MS study, the proposed mechanism of the IV above reaction with the Pt -NPs is depicted in Scheme 3. The functionalized surface of the small NPs was helpful to coordinate the substrates through push-pull mechanism of the three attached ligands (I, Scheme 3) such as two -Br and -OMe, which greatly enhanced the electrophilicity of the carbonyl centre and neucleophilicity of the precursor amine (I-1). Herein, initial nucleophilic attack of the activated amine to more electrophilic keto-carbonyl of cyclopropane and simultaneous C-C coupling with PhCHOMe-Pt generates the seven member cyclic intermediate I-2. Formation of the I-2 intermediate was confirmed by the detection of m/z [M+H] symbolic peak of the corresponding ligand in the ESI-MS spectrum (Supporting Information). The intermediate I-2 obtained through cascade reaction was immediately proceeded through C-N coupled ring expansion reaction with reductive elimination II II of Pt -bound product (I-3) and PhCHO. The desired product 4 was achieved with the elimination procatalyst (Pt ).

7



Page 8 of 23

II

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

Oxidative addition of Pt -species to C-O bond of benzaldehyde dimethylacetal (3a) regenerates the active nanocatalyst I, which is available for the next nanocatalysis cycle.

Figure 4. Mid-IR-ATR 3D-Surface of Ongoing Nanocatalysis Reaction

Figure 5. 2D-IR Spectra at Different Reaction Time Interval with Individual Components PhMe PhCH(OMe)2 +PtBr 2 Oxidative addition OMe PhCH(OMe)2 3a

R2

R3 N

Ph H N

Ph

H N

Ph

PtIV

R3 NH 2 2

Br

Br I

Regeneration of Nanocatalyst R 3 NH2 Ph

4

O Release of product

Ph

3

Ph R2 N H I-3

R2

OMe O 1 O

R N

H N O

MeO C-N/C-O Coupling

O [Pt II]

R3 H C -N N R in C ou g E ple d Ph xp an sio n O

Suface functionalized Ph Pt(IV)-NPs PhCHO Reductive Elimination

R2

O [PtIV ] I-1

MeOH H N

R2

O [PtIV] I-2

Scheme 3. Nanocatalysis Cycle for Synthesis of 2-Pyrrolines

8


Page 9 of 23

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


26

27

Recently depropargylation has found considerable application in the modern biological, material and chemi28 cal sciences. However most of the propargyl amine C-N cleavage approaches have the limitation using multiple reagents, prior preparation and application complexities. It prompted us to examine for developing a simple proIV pargyl amine deprotection strategy exploiting the novel Pt -organometallic nanocatalyst. Thus propargyl amine was employed as a source of nitrogen for direct synthesis of 1-pyrroline (7) through cyclopropane ring expansion including depropargylation (Scheme 4). Gratifyingly a number of valuable 1-pyrrolines (7a-g) were synthesized using 1-benzoyl-N-phenylcyclopropane-carboxamide (1) and propargyl amine (6) in good yield (74-80%) and short reaction time (5-9 h). It is expected that the tandem reaction is passing through the ring opening, cyclization and depropargylation sequence in the presence of the powerful catalyst. However the yield was reduced (65%) for compound 7h in the presence of strong electron withdrawing group in the aromatic ring of amide functionality. IV It is noteworthy that the C9H12Br2O2Pt -NPs are not only found as a robust catalyst for cyclopropane ring expansion to useful 1-pyrrolines, but also for widely used deprotection of propargyl group.

Scheme 4. Synthesis of 1-Pyrrolines (7) with Propargyl Group-Cleavage A reasonable mechanism is proposed in Scheme 5 for the formation of product 1-pyrroline (7). Presumably the IV first step is the activation of propargyl amine through complexation with Pt -NPs (I-4, Scheme 5) and nucleophilic attack to the carbonyl center to form a seven member cyclic complex (I-5). The intermediate immediately undergoes for cleavage of the electrophilic cyclopropane ring and activation of propargyl group to form a five member heterocycle (I-6). The cleavage of propargyl C-N bond and formation of 1-proline occurred simultaneously with IV removal of procatalyst PtBr2 and benzaldehyde. Regeneration of the Pt -organometalic on the surface of NPs is II performed through oxidative insertion of 3a to Pt -species. We have studied the progress of the catalytic process using 3D Mid-IR-ATR spectral analyses of the ongoing reaction among 1-benzoyl-Nphenylcyclopropanecarboxamide (1a) and propargyl aniline (6a) in the presence of PtBr2 and benzaldehyde di-1 methylacetal (3a). With progress of the reaction, a peak at 2133 cm vanishes (corresponding to propargyl -1 amine, red line, Figure 6), whereas the peak for amide group shifted to 1596 cm (brown line, Figure 6).

9



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

PhMe PhCH(OMe) 2+PtBr2 Oxidative addition OMe PhCH(OMe)2 3a

R2

Ph H N O

OMe

PtIV

Ph

H N

Ph

O 1O H2N

Br

Br

Page 10 of 23

R2

2

I N

Regeneration of Nanocatalyst NH 2 Ph

7 Depropargylation with Release of Product

Ph C-N/C-O Coupling MeO H2 C

[Pt IV] Ph

N

[PtIV ] C HC

MeOH R2 HN

O [PtII]

I-6

C -N N R in Co u g E pl e Ph x pa d ns io n O

Ph Suface functionalized PhCHO Pt(IV)-NPs Reductive elimination

H N O

R2

O [Pt IV] I-4

H MeOH H N

R2

O [Pt IV] I-5

Scheme 5. Nanocatalysis Cycle to 1-Pyrrolines with Depropargylation

Figure 6. FTIR spectra of individual reaction components for synthesis of 1-pyrrolines 3

Next, we explored the ability of the NPs for sp C-H activation with dual cyclisation to achieve fused-pyrrolines. Herein, a three component, dual cyclisation through cyclopropane ring-expansion was devised for the direct synthesis of pyrrolo[3,2-c]pyridone compounds (8, Scheme 6) using acylarylaminoformyl cyclopropanes (1), arylamines (2) and dimethylacetal derivatives of arylaldehydes (3). Electron donating and electron withdrawing substituents on aromatic residues were tolerated in this new strategy. A wide range of fused-heterocycles (8a-m) was rapidly (6-7 h) synthesised with good yields (65-78%). The reaction was carried out under similar reaction conditions (entry 3, Table 1) with excess amounts of aryaldehyde dimethylacetals (3a-c, 2 mmol). Herein one molecule of ArCH(OMe)2 is incorporated into the product 8 as ArCH-moiety and second molecule converted into ArCHO. From the outcome, we concluded that electron donating and electron withdrawing substituents on the aromatic ring do not have much influence on the reaction. However, in the presence of methyl substituents on the cyclopropane ring (1h), the steric strain was greatly enhanced in the transition state, which reduced the reaction rate (9 h) and yield (51%) during construction of 8n.

10


Page 11 of 23

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 6. Synthesized fused-2-pyrrolines (8) We propose that Pt-bearing three easily releasable groups (2Br and OMe; I, Scheme 7) in the surface of the NPs binds efficiently 1 leading to coupling with activated amine (2, I-7) to intermediate I-8. The activated seven member cyclic I-8 undergoes cyclopropane ring-expansion, which performed N-C coupling with C-C -bond to IV 3 construct I-9. Gratifyingly the Pt -NPs activated a sp C-H bond in I-9 leading to formation of a seven member cyclic intermediate I-10 on the surface of the nanocatalyst. Reductive elimination of I-10 produces the desired II II product (8) with removal of Pt -species. The procatalyst Pt (VII) in the surface of the NPs immediately undergoes oxidative addition to ArCH(OMe)2 for regeneration of the active catalyst site. Transfer of keto group of 1 (1693

11


Industrial & Engineering Chemistry Research -1

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 12 of 23

-1

cm , decreasing hump) into enamino residue of 5 (1678 cm , increasing hump) is clearly observed in the Mid-IRATR 3D-surface of the ring-expansion nanocatalysis (Fig. 7 and Supporting Information) PhCH3 PhCH(OMe)2+PtBr2 (3a)

OMe Ph

3a

Pt

2

I

2

H N

CH3 R3 NH2 Ph O

R3 N

Ph

R2

+ O 5O Br R NH 2 3

Nanocatalyst regeneration

II

R

Pt Br

X

X

H N

OMe CH3

IV

O 8

MeOH

N

Ph IV

[Pt ]

N O R2

X I-10 Suface functionalized Pt(IV)-NPs

R2

I-7

[PtIV]

MeO

Cyclisation R3

N

O

C-H activated C-C Coupling Ph H MeO

MeOH

R3

R3 N H3C O Ph

N

IV X Pt N X O I-9 R2

N-C/O-C Coupling H H N R2 O [PtIV]

I-8 PhCHO Ring expansion

Scheme 7. Possible mechanism of ring expansion nanocatalysis

Figure 7. Selective part of the 3D ATR-MIR spectra The NPs were recovered by centrifuging the post reaction mixture, washed with toluene (yield 76%) and reused. Yields were consistent up to four cycles. With respect to conventional catalysts, the NPs are superior in terms of simple preparation, low catalyst loading; ease recovery, recycling and diverse catalytic activity to achieve a general synthesis of valuable pyrrolines and their fused-analogues. 2 Carbonylarylaminoformyl cyclopropane substrates (1) bearing EWG, EDG and no substitution (R = Ph) were prepared on treatment of acetoacetanilides (X) and K2CO3 mixture in dry DMF with 1,2-dibromoethane (Y) at am29 bient temperature (Scheme 8). O R1

O

Br N H

(X: 1mmol)

R2 + Br

O

K2CO3 (2mmol) DMF (dry), rt

O

R1

(Y: 1.4mmol)

N H

R2

1

Scheme 8. Synthesis of functionalized cyclopropane substrates (1)

12


Page 13 of 23

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


CONCLUSION IV We introduced a new synthetic approach for the fabrication of high-valent organometallic Pt -nanoparticles through oxidative insertion of metals into the readily available, inexpensive ArCH(OMe)2 at ambient temperature. ArCH(OMe)2 also acts as a good stabiliser for the nanofabrication process and scavenger of water generated in situ from the ring-expansion nanocatalysis reaction. SEM, EDS, TEM-EELS, XPS, ESI-MS and other modern instrumental techniques were utilised to establish the size, shape, composition and oxidation state of the functionalIV ised Pt -NPs. A facile, simple and rapid nanocatalysis was demonstrated for the first time for diverse cyclopropane ring expansion to a general synthesis of functionalised 2-pyrrolines, 1-pyrrolines and fused-pyrrolines. It is interesting to note that the same catalytic system performs three different cyclisations and depropargylation reactions, easily recovered and recycled. The reaction insight was investigated thoroughly using 3D-MIR-ATR study, ESI-MS and control experiments. The new nanofabrication strategy through oxidative insertion to novel organometallic-NPs, diverse cyclopropane ring expansion, depropargylation nanocatalysis, 3D-MIR-ATR study and general synthesis of three series of valuable pyrrolines have fundamental significance and will influence future research in chemical and nano-sciences. EXPERIMENTAL SECTION General Method. All reagents were purchased from commercial suppliers and used without further purification, unless otherwise specified. Commercially supplied ethyl acetate and petroleum ether were distilled before use. DMSO was dried by distillation through activated 4Ao molecular sieves. Petroleum ether used in our experiments was in the boiling range of 6080 °C. Column chromatography was performed on silica gel (60-120 mesh), neutral alumina (100-200 mesh) and basic alumina (100-200 mesh). Analytical thin layer chromatography (TLC) was performed on 0.25 mm extra hard silica gel plates with UV254 fluorescent indicator. 1H NMR and 13C NMR spectra were recorded in CDCl3/DMSO-d6 solution at ambient temperature using 300 MHz spectrometers (300 MHz for 1H and 75 MHz for 13C). Chemical shift is reported in ppm from internal reference tetramethylsilane and coupling constant in Hz. Proton multiplicities are represented as s (singlet), d (doublet), dd (double doublet), t (triplet), q (quartet), and m (multiplet). Infrared spectra were recorded on FT-IR spectrometer in thin film. HR-MS data were acquired by electron spray ionization technique on a Q-tof-micro quadrupole mass spectrophotometer. General Procedure for Syntheses of 2-Pyrrolines (GP-I) 4a-f. A solution of 1-benzoyl-N-arylcyclopropanecarboxamide (1, 1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol, 152 mg) and amine (2, 1.0 mmol) in toluene (10 mL) was stirred at 0 0C. PtBr2 (7 mg, 2 mol %) was added to it and the solution was gradually warmed to ambient temperature and during this period (~ 30 min) the desired Ph(OMe)HCPtIVOMe NPs (~ 3 nm dimension) were fabricated. The reaction mixture was refluxed until all starting materials were consumed. The solution was cool down to ambient temperature and filtered through a small pad of celite. The solution was concentrated in a rotary evaporator under reduced pressure at room temperature. Finally, it was purified by column chromatography (neutral alumina, 100-200 mesh) using different proportion of ethyl acetatepetroleum ether mixture as eluents. 2-Diphenyl-1-p-tolyl-4,5-dihydro-1H-pyrrole-3-carboxamide (4a). The compound was prepared following the GP-I employing 1-benzoyl-N-phenylcyclopropanecarboxamide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and p-toluidine (1.0 mmol). Purification by the column chromatography (6% ethyl acetate-petroleum ether) afforded the title compound as yellow solid (276 mg, 0.78 mmol, 78% yield): mp 122-126 ᴼC; 1H NMR (300 MHz, CDCl3): δ 2.10 (3H, s), 3.06 (2H, t, J = 9.9 Hz), 3.95 (2H, t, J = 9.9 Hz), 6.46-6.53 (1H, m), 6.77-6.88 (2H, m), 6.95 (1H, d, J = 3.2 Hz), 7.06 (1H, t, J = 7.5 Hz), 7.267.29 (1H, m), 7.34-7.39 (1H, m); 13C NMR (75 MHz, CDCl3): δ 14.6, 23.1, 47.1, 102.7, 109.2, 112.5, 115.5, 116.6, 122.6, 123.1, 123.2, 123.7, 123.8, 125.7, 126.4, 132.7, 134.1, 145.8, 158.2; FT-IR (KBr, cm-1): 718, 1120, 1231, 1398, 1473, 1545, 1659, 2978, 3289; HRMS (ESI-TOF) m/z calcd for C24H22N2O [M+H] 355.1810, found 355.1807. 1-Benzyl-2-methyl-N-phenyl-4,5-dihydro-1H-pyrrole-3-carboxamide (4b). The compound was prepared following the GPI employing 1-benzoyl-N-phenylcyclopropanecarboxamide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and benzyl amine (1.0 mmol). Purification by the column chromatography (7% ethyl acetate-petroleum ether) afforded the title compound as off-white solid (213 mg, 0.74 mmol, 74% yield): mp 144-148 ᴼC; 1H NMR (300 MHz, CDCl3) δ 2.34 (3Η, s), 2.69 (2H, t, J = 9.6 Hz), 3.29 (2H, t, J = 9.6 Hz), 4.22 (2H, s), 7.10-7.28 (8H, m), 7.42 (4H, d, J = 4.05 Hz); 13C NMR (75 MHz, CDCl3) δ 12.2, 27.4, 50.4, 50.6, 98.1, 119.7, 122.9, 127.2, 127.5, 127.8, 128.7, 128.7, 128.9, 137.3, 139.2, 160.3, 165.4; FTIR (KBr, cm-1): 731, 1178, 1243, 1442, 1544, 1597, 1652, 1671, 2923, 3250; HRMS (ESI-TOF) m/z calcd for C19H20N2O [M+H] 293.1654, found 293.1651.

13



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 14 of 23

N-2-Diphenyl-1-m-tolyl-4,5-dihydro-1H-pyrrole-3-carboxamide (4c). The compound was prepared following the GP-I employing 1-benzoyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and meta-toluidine (1.0 mmol). Purification by the column chromatography (7% ethyl acetate-petroleum ether) afforded the title compound as colourless solid (240 mg, 0.68 mmol, 68% yield): mp 132-136 ᴼC; 1H NMR (300 MHz, CDCl3) δ 2.07 (3H, s), 3.06 (2H, t, J = 9.9 Hz), 3.98 (2H, t, J = 10.2 Hz), 6.32 (1H, d, J = 4.0 Hz), 6.39 (1H, s), 6.54-6.62 (2H, m), 6.81-6.86 (2H, m), 6.95-6.97 (2H, m), 7.04-7.09 (2H, m), 7.28-7.38 (2H, m); 13C NMR (75 MHz, CDCl3) δ 21.4, 29.2, 52.9, 109.4, 118.3, 118.6, 121.9, 122.7, 123.42, 128.3, 128.5, 128.7, 129.3, 129.9, 131.8, 138.4, 142.6, 151.4, 164.3; FT-IR (KBr, cm-1): 712, 1003, 1162, 1321, 1443, 1535, 1650, 1694, 3340; HRMS (ESI-TOF) m/z calcd for C24H22N2O [M+H] 355.1810, found 355.1806. 1-Benzyl-N-2-diphenyl-4,5-dihydro-1H-pyrrole-3-carboxamide (4d). The compound was prepared following the GP-I employing 1-benzoyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and benzyl amine (1.0 mmol). Purification by the column chromatography (9% ethyl acetate-petroleum ether) afforded the title compound as pale yellow solid (265 mg, 0.75mmol, 75% yield): mp 140-144 ᴼC; 1H NMR (300 MHz, CDCl3) δ 2.95 (2H, t, J = 9.9 Hz), 3.35 (2H, t, J = 10.2 Hz), 3.88 (2H, s), 6.81 (1H, t, J = 7.5 Hz), 6.93 (2H, d, J = 3.9 Hz), 7.02-7.11 (4H, m), 7.17-7.26 (4H, m), 7.37-7.40 (2H, m), 7.47-7.48 (2H, m); 13C NMR (75MHz, CDCl3) δ 28.8, 50.6, 52.6, 118.5, 122.4, 127.4, 127.5, 128.6, 128.6, 129.3, 129.7, 130.1, 137.6, 139.0, 145.2, 157.8; FT-IR (KBr, cm-1): 693, 1177, 1243, 1441, 1524, 1598, 1661, 1732, 2924, 3406; HRMS (ESI-TOF) m/z calcd for C24H22N2O [M+H] 355.1810, found 355.1807. 1-Benzyl-N-(4-isopropylphenyl)-2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxamide (4e). The compound was prepared following the GP-I employing 1-benzoyl-cyclopropanecarboxylic acid (4-isopropylphenyl)-amide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and benzyl amine (1.0 mmol). Purification by the column chromatography (6% ethyl acetatepetroleum ether) afforded the title compound as white solid (275 mg, 0.70 mmol, 70% yield): mp 119-123 ᴼC; 1H NMR (300 MHz, CDCl3) δ 1.21−1.29 (6Η, m), 2.84-2.86 (1H, m), 3.09 (2H, t, J = 9.6 Hz), 3.45 (2H, t, J = 6.3 Hz), 4.01 (2H, s), 6.62 (1H, s), 7.01-7.08 (4H, m), 7.12-7.41 (5H, m), 7.51-7.54 (2H, m), 7.59-7.62 (3H, m); 13C NMR (75 MHz, CDCl3) δ 24.0, 28.8, 33.4, 50.6,52.6, 104.97, 118.62 119.2, 126.4, 126.5, 126.6, 127.3, 127.4, 127.5, 127.5,127.6,127.6, 128.5, 128.6, 128.68, 129.2, 129.3, 129.4, 129.6, 130.0, 132.0, 136.7, 137.6, 143.1, 156.0, 164.0; FT-IR (KBr, cm-1): 691, 716, 1134, 1280, 1464, 1550, 1676, 1719, 2908, 3230; HRMS (ESI-TOF) m/z calcd for C27H28N2O [M+H] 397.2280, found 397.2284. 1-(4-methylbenzyl)-N-2-diphenyl-4,5-dihydro-1H-pyrrole-3-carboxamide (4f). The compound was prepared following the GP-I employing 1-Benzoyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and p-methyl benzyl amine (1.0 mmol). Purification by the column chromatography (7% ethyl acetate-petroleum ether) afforded the title compound as white solid (276 mg, 0.76 mmol, 76% yield): mp 125-128 ᴼC; 1H NMR (300 MHz, CDCl3) δ 2.31 (3Η, s), 3.01 (2H, t, J = 10.8 Hz), 3.39 (2H, t, J = 10.5 Hz), 3.90 (2H, s), 6.56 (1H, s), 6.87-6.89 (1H, m), 7.00-7.13 (8H, m), 7.43-7.46 (2H, m), 7.53-7.54 (3H, m); 13C NMR (75 MHz, CDCl3) δ 21.00, 28.64, 50.32, 51.10, 104.49, 118.36, 122.28, 127.37, 128.58, 129.16, 129.20, 129.58, 130.00, 131.87, 134.32, 137.00, 138.97, 156.25, 164.07; FT-IR (KBr, cm-1): 722, 1135, 1256, 1478, 1530, 1637, 2955, 3408; HRMS (ESI-TOF) m/z calcd for C25H25N2O [M+H] 369.1967, found 369.1971. 1-(4-Fluorobenzyl)-N-2-diphenyl-4,5-1H-pyrrole-3-carboxamide (4g). The compound was prepared following the GP-I employing 1-Benzoyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and pfluorobenzyl amine (1.0 mmol). Purification by the column chromatography (8% ethyl acetate-petroleum ether) afforded the title compound as light yellow oil (252 mg, 0.68 mmol, 68% yield). 1H NMR (300 MHz, CDCl3) δ 2.96 (2H, t, J = 10.5 Hz), 3.34 (2H, t, J = 10.2 Hz), 3.86 (2H, s), 6.52 (1H, s), 6.84 (1H, t, J = 6.3Hz), 6.92-6.98 (4H, m), 7.06-7.10 (4H, m), 7.41 (2H, m), 7.51-7.3 (3H, m);13C NMR (75 MHz, CDCl3) δ 28.7, 50.6, 51.9, 105.2, 115.3, 115.6, 118.5, 122.5, 128.7, 129.0, 129.2, 129.7, 130.1, 131.8, 133.2, 138.8, 156.0, 163.7,163.9; FT-IR (neat, cm-1): 726, 1221, 1275, 1480, 1576, 1640, 2934; HRMS (ESI-TOF) m/z calcd for C24H22FN2O [M+H] 373.1716, found 373.1721. General Procedure for Syntheses of 1-Pyrrolines (GP-II) 7a-h. A solution of 1-benzoyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and propargyl amine (1.5 mmol, 82.0 mg) in toluene (10 mL) was stirred at 0 ᴼC. Platinum(II) bromide (7 mg, 2 mol %) was added to it and the solution was warmed gradually to ambient temperature. It was heated to reflux until all starting materials were consumed. The solution was allowed to come to room temperature and filtered through a small pad of celite. The solution was concentrated in a rotary evaporator under reduced pressure at room temperature. Finally, it was purified by column chromatography (neutral alumina, 100-200 mesh) using different proportion of ethyl acetate-petroleum ether mixture as eluent. 2-Phenyl-4,5-dihydro-3H-pyrrole-3-carboxylic acid phenylamide (7a). The compound was prepared following the GP-II employing 1-benzoyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and

14


Page 15 of 23

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


propargyl amine (1.5 mmol). Purification by the column chromatography (8% ethyl acetate-petroleum ether) afforded the title compound as off-white solid (195 mg, 0.74 mmol, 74% yield): mp 140-144 ᴼC; 1H NMR (300 MHz, DMSO-D6) δ 2.01−2.09 (1Η, m), 2.22−2.29 (1Η, m), 3.93 (2H, t, J = 6.6 Hz), 4.20-4.25 (1H, m), 6.91-6.96 (1H, m), 7.18 (3H, t, J = 8.1 Hz), 7.30-7.32 (3H, m), 7.44-7.47 (2H, m), 7.73-7.75 (1H, m), 10.32 (1H, m); 13C NMR (75MHz, DMSOD6) δ 30.1, 55.1, 60.9, 119.7, 123.9, 127.8, 128.9, 129.0, 129.2, 130.7, 134.3, 139.3, 170.0, 171.0; FT-IR (KBr, cm-1): 572, 687, 1075, 1242, 1470, 1532, 1667, 3284; HRMS (ESI-TOF) m/z calcd for C17H17N2O [M+H] 265.1341, found 265.1346. 2-Phenyl-4,5-dihydro-3-carboxylic acid p-tolylamide (7b). The compound was prepared following the GP-II employing 1benzoyl-cyclopropanecarboxylic acid p-tolylamide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and propargyl amine (1.5 mmol). Purification by the column chromatography (8% ethyl acetate-petroleum ether) afforded the title compound as light yellow solid (216 mg, 0.78 mmol, 78% yield): mp 132-134 ᴼC; 1H NMR (300 MHz, CDCl3) δ 2.18 (3Η, s), 2.21-2.28 (2H, m), 4.00-4.07 (3H, m), 6.94 (2H, d, J = 4.2 Hz), 7.19 (2H, d, J = 3.6 Hz), 7.22-7.31 (2H, m), 7.75 (2H, d, J = 13 3.6 Hz), 8.07 (1H, s); C NMR (75 -1 MHz,CDCl3) δ 20.8, 29.9, 56.1, 60.9, 120.4, 127.7, 128.7, 129.4, 130.7,133.5, 134.4, 170.3, 170.5; FT-IR (KBr, cm ): 690, 1245,1347, 1446, 1494, 1595, 1651, 2971, 3414; HRMS (ESI-TOF) m/z calcd for C18H19N2O [M+H] 279.1497, found 279.1502. 2-Phenyl-4,5-dihydro-3H-pyrrole-3-carboxylic acid (4-ethylphenyl)-amide (7c). The compound was prepared following the GP-II employing 1-benzoyl-cyclopropanecarboxylic acid (4-ethyl-phenyl)-amide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and propargyl amine (1.5 mmol). Purification by the column chromatography (8% ethyl acetate-petroleum ether) afforded the title compound as off-white solid (235 mg, 0.81 mmol, 81% yield): mp 120-124 ᴼC; 1H NMR (300 MHz, CDCl3) δ 1.27 (3H, t, J = 7.8 Hz), 2.38 (2H, t, J = 6.9 Hz), 2.62 (2H, q, J = 7.5Hz ), 4.14-4.24 (3H, m), 7.12 (2H, d, J = 4.2 13 Hz), 7.32-7.45 (5H, m), 7.87-7.89 (2H, m); C NMR (75 MHz, CDCl3) δ 15.6, 28.3, 29.9, 56.2, 60.9, 102.3, 127.8, 128.3, 128.8, 130.8, 133.4, 135.2, 140.8, 170.3,170.5; FT-IR (KBr, cm-1): 567, 621, 1114, 1248, 1402, 1639, 3222; HRMS (ESI-TOF) m/z calcd for C19H20N2O [M+H] 293.1654, found 293.1658. 2-Phenyl-4,5-dihydro-3H-pyrrole-3-carboxylic acid (4-bromophenyl)-amide (7d). The compound was prepared following the GP-II employing 1-benzoyl-cyclopropanecarboxylic acid (4-bromo-phenyl)-amide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and propargyl amine (1.5 mmol). Purification by the column chromatography (9% ethyl acetate-petroleum ether) afforded the title compound as light-yellow solid (256 mg, 0.75 mmol, 75% yield): mp 130-134 ᴼC; 1H NMR (300 MHz, DMSO-D6) δ 1.97−2.06 (1Η, m), 2.23−2.30 (1Η, m), 3.93 (2H, t, J = 6.6 Hz), 4.19-4.23 (1H, m), 7.27-7.45 (7H, m), 7.7013 7.7.73 (2H, m), 10.46 (1H, s); C NMR (75 MHz, DMSOD6) δ 29.1, 54.1, 59.9, 114.6, 120.7, 126.8, 127.9, 129.7, 131.0, 133.2, 137.7, 168.9, 170.2;FT-IR (KBr, cm-1): 696, 1008, 1344, 1490, 1516, 1655, 3293; HRMS (ESI-TOF) m/z calcd for C17H16BrN2O [M+H] 343.0446, found 343.0450. (one of the peaks). 2-Phenyl-4,5-dihydro-3H-pyrrole-3-carboxylic acid (4-bromo-3-methylphenyl)-amide (7e). The compound was prepared following the GP-II employing 1-benzoyl-cyclopropanecarboxylic acid (4-bromo-3-methyl-phenyl)-amide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and propargyl amine (1.5 mmol). Purification by the column chromatography (10% ethyl acetate-petroleum ether) afforded the title compound as yellow solid (203 mg, 0.77 mmol, 77% yield): mp 126-130 ᴼC; 1 H NMR (300 MHz, CDCl3) δ 1.98−2.09 (5Η, m), 3.89-3.97 (3H, m), 6.86-6.89 (1H, m), 7.09-7.16 (4H, m), 7.19-7.24 (1H, 13 m), 7.59 (2H, d, J = 3.6 Hz), 9.235(1H, s); C NMR (75 MHz, CDCl3) δ 22.7, 29.62, 55.26, 60.29, 119.25, 119.70, 122.49, 127.43, 18.01, 128.47, 130.59, 132.23, 132.81, 133.12, 136.78, 138.24, 140.16, 170.64, 171.11; FT-IR (KBr, cm-1): 581, 694, 1156, 1388, 1473, 1648, 3230; HRMS (ESI-TOF) m/z calcd for C18H18BrN2O [M+H] 357.0603, found 357.0608. (One of the major peaks). N-(4-Iodophenyl)-5-phenyl-3,4-dihydro-2H-pyrrole-4-carboxamide (7f). The compound was prepared following the GP-II employing 1-benzoyl-cyclopropanecarboxylic acid (4-iodo-phenyl)-amide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and propargyl amine (1.5 mmol). Purification by the column chromatography (12% ethyl acetate-petroleum ether) afforded the title compound as white solid (270 mg, 0.70 mmol, 70%): mp 148-151 ᴼC; 1H NMR (300 MHz, DMSOD6) δ 2.03-2.09 (1H, m), 2.25-2.32 (1H, m), 3.96 (2H, t, J = 6.6 Hz), 4.24-4.28 (1H, m), 7.31-7.34 (5H, m), 7.54 (2H, d, J = 13 4.3Hz), 7.74-7.76 (2H, m), 10.49 (1H, s); C NMR (75 MHz, DMSOD6) δ 29.1, 54.2, 60.0, 86.5,1 20.9, 126.8, 127.9, 129.8, 133.2, 138.2, 168.9, 170.3; FT-IR (KBr, cm-1): 654, 1228, 1456, 1535, 1646, 3257; HRMS (ESI-TOF) m/z calcd for C17H16IN2O [M+H] 391.0307, found 391.0311. (One of the major peaks). N-(4-Chloro-3-(trifluoromethyl)phenyl)-5-phenyl-3,4-dihydro-2H-pyrrole-4-carboxamide (7g). The compound was prepared following the GP-II employing 1-Benzoyl-cyclopropanecarboxylic acid (4-chloro-3-trifluoromethyl-phenyl)-amide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and propargyl amine (1.5 mmol). Purification by the column chromatog-

15



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 16 of 23

raphy (11% ethyl acetate-petroleum ether) afforded the title compound as light yellow solid (259 mg, 0.70 mmol, 70% yield): mp 142-146 ᴼC; 1H NMR (300 MHz, DMSO-D6) δ 2.11−2.17 (1Η, m), 2.32−2.46 (1Η, m), 4.02 (2H, t , J = 6.6 Hz), 4.31-4.34 (1H, m), 7.36-7.38 (3H, m), 7.57 (2H, d, J = 4.5 Hz), 7.78-7.81 (3H, m),8.13-8.14 (1H, m), 10.87 (1H, s); 13C NMR (75 MHz, DMSOD6) δ 29.3, 54.3, 60.1, 117.3, 117.4, 120.4, 125.8, 126.2, 126.6, 126.9, 127.4, 128.1, 129.9, 131.7, 133.2, 137.8, 168.8, 170.9 ; FT-IR (KBr, cm-1): 584, 668, 1058, 1260, 1452, 1656, 3257; HRMS (ESI-TOF) m/z calcd for C17H15ClFN2O [M+H] 367.0825, found 367.0830. (One of the major peaks). N-(3-Chloro-4-fluorophenyl)-5-phenyl-3,4-dihydro-2H-pyrrole-4-carboxamide (7h). The compound was prepared following the GP-II employing 1-benzoyl-cyclopropanecarboxylic acid (3-chloro-4-fluoro-phenyl)-amide (1.0 mmol), benzaldehyde dimethyl acetal (1.0 mmol) and propargyl amine (1.5 mmol). Purification by the column chromatography (12% ethyl acetatepetroleum ether) afforded the title compound as off-white solid (206 mg, 0.65 mmol, 65%): mp 136-140 ᴼC; 1H NMR (300 MHz, DMSO-D6) δ 1.93−2.11 (1Η, m), 2.24−2.36 (1Η, m), 3.97 (2H, t, J = 6.6 Hz) , 4.22-4.24 (1H, m), 7.24-7.39 (5H, m), 13 7.75-7.81 (3H, m), 10.57 (1H, s); C NMR (75 MHz, DMSOD6) δ 29.2, 54.1, 60.0, 116.3, 116.6, 118.8, 119.0, 199.1, 120.1, 126.7, 128.0, 129.8, 133.2, 135.6, 168.8, 170.4; FT-IR (KBr, cm-1): 566, 665, 1218, 1401, 1499, 1642, 2097, 3408; HRMS (ESI-TOF) m/z calcd for C17H15ClFN2O [M+H] 317.0857, found 317.0861. (one of the major peaks). General Procedure for Syntheses of Pyrrolo[3,2-c]pyridines (GP-III) 8a-m. A solution of acetyl-N-(4-bromo-3methylphenyl)cyclopropanecarboxamide (1.0 mmol), benzaldehyde dimethyl acetal (2 mmol) and aniline derivative (1.0 mmol) in toluene (10 mL) was stirred at 0 ᴼC. PtBr2 (7 mg, 2 mol%) was added to it and the solution were warmed to ambient temperature slowly. It was heated to reflux until all starting materials were consumed. The solution was allowed to come to room temperature and filtered through a small pad of celite. The solution was concentrated in a rotary evaporator under reduced pressure at room temperature. Finally, it was purified by column chromatography (neutral alumina, 100-200 mesh) using different proportion of ethyl acetate-petroleum ether mixture as eluent. 5-(4-Bromo-3-methylphenyl)-1-(4-isopropylphenyl)-6-phenyl-1,2,3,5,6,7-hexahydropyrrolo[3,2-c]pyridine-4-one (8a). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid (4-bromo-3-methylphenyl)amide (1.0 mmol), benzaldehyde dimethyl acetal (2 mmol) and 4-isopropylaniline (1.0 mmol). Purification by the column chromatography (12% ethyl acetate-petroleum ether) afforded the title compound as pale yellow solid (365 mg, 0.73 mmol, 73% yield): mp 92-96 ᴼC; 1H NMR (300 MHz, CDCl3) δ 1.12-1.19 (6H, m), 2.15 (3H, s), 2.73-2.93 (4H, m), 3.29 (1H, dd, J = 6.6Hz, 16.5Hz ), 3.81-3.91 (2H, m), 5.01-5.04 (1H, m), 6.69-6.75 (3H, m), 6.98-7.01 (3H, m), 7.05-7.25 (6H, m); 13C NMR (75 MHz, CDCl3) δ 22.9, 23.9, 24.1, 25.5, 32.3, 33.5, 53.6, 62.4, 105.5, 119.5, 120.7, 124.3, 126.6, 127.0, 127.1, 127.2, 127.6, 128.3, 128.7, 132.1, 132.2, 136.8, 137.9, 138.8, 138.9, 140.8, 141.7, 144.4, 153.7, 166.0;FT-IR (KBr, cm-1): 698, 1026, 1411, 1454, 1477, 1516, 1605, 1708, 2957; HRMS (ESI-TOF) m/z calcd for C29H29BrN2O [M+H] 501.1542, found 501.1538. (one of the major peaks). 6-(4-Methoxyphenyl)-5-phenyl-1-p-tolyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8b). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), p-methoxy benzaldehyde dimethyl acetal (2 mmol) and p-toluidine (1.0 mmol). Purification by the column chromatography (12% ethyl acetate-petroleum ether) afforded the title compound as yellow solid (320 mg, 0.78 mmol, 78% yield): mp 140-142 ᴼC; 1H NMR (300 MHz, CDCl3) δ 2.27 (3Η, s), 2.75−2.96 (3Η, m), 3.28−3.36 (1Η, m), 3.74 (3Η, s), 3.84-3.92 (2H, m), 5.07-5.10 (1H, m), 6.71-6.78 (4H, m), 7.02-7.08 (4H, m), 7.14-7.23 (5H, m); 13C NMR (75 MHz, CDCl3) δ 20.6, 25.5, 32.4, 53.5, 55.1, 61.8, 105.9, 113.8, 120.5, 124.7, 125.4, 127.7, 128.3, 129.7, 132.9, 133.1, 138.9, 142.7, 153.1, 158.7, 165.8; FT-IR (KBr, cm-1): 709, 1105, 1364, 1472, 1643, 3268; HRMS (ESI-TOF) m/z calcd for C27H26N2NaO2 [M+Na] 433.1892, found 433.1896. 5-(4-Chlorophenyl)-6-phenyl-1-p-tolyl-2,3,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4(5H)-one (8c). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid (4-chlorophenyl)-amide (1.0 mmol), benzaldehyde dimethyl acetal (2 mmol) and p-toluidine (1.0 mmol). Purification by the column chromatography (10% ethyl acetatepetroleum ether) afforded the title compound as yellow solid (257 mg, 0.69 mmol, 69%): mp 144-148 ᴼC; 1H NMR (300 MHz, CDCl3) δ 2.20 (3H, s), 2.73-2.88 (3H, m), 3.25-3.37 (1H, m), 3.79-4.04 (2H, m), 5.02-504 (1H, m), 6.64-6.67 (2H, m), 6.98-7.09 (6H, m), 7.16-7.17 (5H, m); 13C NMR (75 MHz, CDCl3) δ 20.7, 25.5, 32.3, 53.7, 62.3, 105.7, 120.8, 126.6, 126.6, 127.6, 128.4, 128.7, 129.8, 130.1, 133.4, 138.8, 140.9, 141.2, 153.5, 165.8; FT-IR (KBr, cm-1): 695, 1245, 1439, 1520, 1647, 2953, 3410; HRMS (ESI-TOF) m/z calcd for C26H23ClN2O [M+H] 415.1577, found 415.1581. (one of the major peaks). 5-(4-Ethylphenyl)-6-phenyl-1-p-tolyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8d). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid (4-ethylphenyl)amide (1.0 mmol), benzaldehyde

16


Page 17 of 23

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


dimethyl acetal (2 mmol) and p-toluidine (1.0 mmol). Purification by the column chromatography (10% ethyl acetatepetroleum ether) afforded the title compound as brown solid (292 mg, 0.72 mmol, 72% yield): mp 98-102 ᴼC; 1H NMR (300 MHz, CDCl3) δ 1.09 (3Η, t, J = 7.5 Hz), 2.23 (3H, s), 2.48 (2H, q, J = 7.5 Hz), 2.75-2.93(3H, m), 3.25-3.34 (1H,m), 3.793.91 (2H, m), 5.07-5.11 (1H, m), 6.68 (2H, d, J = 4.2 Hz), 6.93-7.00 (6H, m), 7.03-7.22 (5H, m); 13C NMR (75 MHz, CDCl3) δ 15.2, 20.6, 25.5, 28.1, 32.1, 53.5, 62.3, 105.8, 119.2, 119.2, 120.6, 125.3, 126.5, 127.3, 127.8, 128.0, 128.9, 129.7, 133.0, 137.0, 138.9, 140.1, 140.9, 141.1, 153.1, 153.6, 165.9; FT-IR (KBr, cm-1): 701, 1242, 1408, 1454, 1514, 1634, 2926, 3434; HRMS (ESI-TOF) m/z calcd for C28H28N2O [M+H] 409.2280, found 409.2275. 5-(4-Chlorophenyl)-1-(4-ethylphenyl)-6-phenyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8e). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid (4-chlorophenyl)amide (1.0 mmol), benzaldehyde dimethyl acetal (2.2 mmol) and p-ethyl aniline (1.0 mmol). Purification by the column chromatography (10% ethyl acetate-petroleum ether) afforded the title compound as brown solid (298 mg, 0.70 mmol, 70% yield): mp 112-116 ᴼC; 1 H NMR (300 MHz, CDCl3) δ 1.14 (3Η, t, J = 7.5 Ηz), 2.50 (2Η, q, J = 7.5 Hz), 2.75-2.92 (3H, m), 3.24-3.32 (1H, m), 3.803.89 (2H, m), 5.01-5.04 (1H, m), 6.69 (2H, d, J = 4.2 Hz), 6.96-7.09 (7H, m), 7.14-7.19 (4H, m); 13C NMR (75 MHz, CDCl3) δ 15.5, 25.5, 28.1, 30.9, 32.4, 53.7, 62.3, 105.6, 115.3, 120.1, 120.8, 126.6, 126.7, 127.6, 128.2, 128.5, 128.6, 128.7, 130.2, 138.9, 139.8, 140.8, 141.2, 153.6, 165.9; FT-IR (KBr, cm-1): 723, 1179, 1250, 1365, 1480, 1664, 2930, 3417; HRMS (ESITOF) m/z calcd for C27H28N2O [M+H] 429.1734, found 429.1730. 5,6-Diphenyl-1-p-tolyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8f). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), benzaldehyde dimethyl acetal (2 mmol) and p-toluidine (1.0 mmol). Purification by the column chromatography (10% ethyl acetate-petroleum ether) afforded the title compound as brown solid (245 mg, 0.65 mmol, 65% yield): mp 131-135 ᴼC; 1H NMR (300 MHz, CDCl3) δ 2.21 (3Η, s), 2.77-2.97 (3H, m), 3.33 (1H, dd, J = 6.3Hz, 16.8Hz), 3.80-3.92 (2H, m), 5.10-5.13 (1H, m), 6.69 (2H, d, J = 4.2 Hz), 6.94-7.02 (2H, m), 7.13-7.21 (10H, m); 13C NMR (75 MHz, CDCl3) δ 20.6, 25.5, 32.2, 53.6, 62.3, 105.7, 119.0, 119.3, 120.7, 121.8, 124.9, 125.5, 126.6, 127.4, 128.4, 128.5, 129.1, 129.8, 133.2, 138.8, 141.1, 142.6, 153.4, 166.0; FT-IR (KBr, cm-1): 687, 1239, 1405, 1516, 1644, 3244; HRMS (ESI-TOF) m/z calcd for C26H24N2O [M+H] 381.1967, found 381.1961. 5-(4-Chlorophenyl)-1-(4-isopropylphenyl)-6-phenyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8g). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid (4-chlorophenyl)amide (1.0 mmol), benzaldehyde dimethyl acetal (2 mmol) and 4-isopropyl aniline (1.0 mmol). Purification by the column chromatography (12% ethyl acetate-petroleum ether) afforded the title compound as light brown solid (322 mg, 0.73 mmol, 73%): mp 112-115 ᴼC; 1H NMR (300 MHz, CDCl3) δ 1.07-1.22 (6H, m), 2.75-2.94 (4H, m), 3.65 (1H, dd, J = 6.0Hz, 16.5Hz), 3.843.93 (2H, m), 5.06 (bs), 6.73 (2H, d, J = 3.6 Hz), 7.01-7.08 (6H, m), 7.14-7.22 (5H, m); 13C NMR (75MHz, CDCl3) δ 23.9, 24.0, 25.5, 32.3, 33.4, 53.6, 62.3, 105.3, 119.6, 120.1, 120.7, 126.6, 126.8, 127.2, 127.6, 128.5, 128.6, 130.3, 138.9, 140.7, 141.0, 144.4, 153.7, 166.0; FT-IR (KBr, cm-1): 726, 1137, 1219, 1403, 1644, 3413; HRMS (ESI-TOF) m/z calcd for C28H27ClN2O [M+H] 443.1890, found 443.1894. (One of the major peaks). 5-(4-Bromophenyl)-6-phenyl-1-p-tolyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8h). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid (4-bromophenyl)amide (1.0 mmol), benzaldehyde dimethyl acetal (2 mmol) and p-toluidine (1.0 mmol). Purification by the column chromatography (10% ethyl acetate-petroleum ether) afforded the title compound as yellow solid (325 mg, 0.71 mmol, 71%): mp 145-148 ᴼC; 1H NMR (300 MHz, CDCl3) δ 2.23 (3Η, s), 2.76−2.93 (3Η, m), 3.28−3.35 (1Η, m), 3.82-3.93 (2H, m), 5.07-5.09 (1H, m), 6.69 (2H, d, J = 4.2 Hz), 6.99-7.04 (4H, m), 7.16-7.26 (7H, m); 13C NMR (75MHz, CDCl3) δ 20.4, 25.2, 31.9, 53.3, 59.9, 61.8, 105.1, 117.4, 120.5, 126.2, 126.7, 127.3, 128.3, 129.0, 129.5, 130.9, 131.3, 133.0, 138.4, 140.5, 141.5, 153.3, 165.3; FT-IR (KBr, cm-1): 706, 1169, 1287, 1465, 1658, 2913, 3406; HRMS (ESI-TOF) m/z calcd for C27H28N2O [M+H] 459.1072, found 459.1077 (one of the major peaks). 5,6-Diphenyl-1-m-tolyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8i). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), benzaldehyde dimethyl acetal (2 mmol) and m-toluidine (1.0 mmol). Purification by the column chromatography (11% ethyl acetate-petroleum ether) afforded the title compound as yellow oil (295 mg, 0.78 mmol, 78% yield). 1H NMR (300 MHz, CDCl3) δ 2.21 (3Η, s), 2.75−2.93 (3Η, m), 3.28-3.35 (1H, m), 3.79-3.89 (2H, m), 5.08-5.09 (1H, m), 6.56 (2H, d, J = 5.4 Hz), 6.75 (1H, d, J = 3.75 Hz), 6.96-7.02 (2H, m), 7.04-7.18 (9H, m);13C NMR (75MHz, CDCl3) δ 21.5, 25.6, 29.7, 32.5, 53.5, 62.4, 106.8, 117.7, 121.1, 124.1, 124.9, 125.5, 126.7, 127.4, 128.4, 128.6, 129.0, 139.2, 141.2, 141.6, 142.6, 152.8, 165.8; FT-IR (neat, cm-1): 720, 1106, 1243, 1329, 1406, 1638, 3416; HRMS (ESI-TOF) m/z calcd for C26H24N2O [M+H] 381.1967, found 381.1963.

17



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 18 of 23

1-(4-Ethylphenyl)-6-(4-(hydroxymethyl)phenyl)-5-phenyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8j). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), benzaldehyde dimethyl acetal (2 mmol) and p-ethyl aniline (1.0 mmol). Purification by the column chromatography (11% ethyl acetate-petroleum ether) afforded the title compound as brown solid (284 mg, 0.72 mmol, 72% yield): mp 132-136 ᴼC; 1 H NMR (300 MHz, CDCl3) δ 1.21 (3Η, t, J = 6.9 Hz), 2.55 (2H, q, J = 7.5 Hz), 2.75-2.97 (3H, m), 3.27-3.33 (1H,m), 3.71 (3H, s), 3.76-3.95 (2H, m), 5.05-5.08 (1H, m), 6.74 (3H, d, J = 3.9 Hz), 6.98-7.11 (7H, m), 7.14-7.24 (3H, m); 13C NMR (75MHz, CDCl3) δ 15.5, 25.6, 28.1, 29.7, 32.5, 53.6, 55.2, 61.9, 105.8, 116.9, 119.2, 119.7, 120.7, 125.0, 125.6, 127.8, 128.0, 128.4, 128.6, 129.1, 133.1, 139.1, 139.5, 139.6, 142.7, 153.5, 153.5, 158.8, 166.1. FT-IR (KBr, cm-1): 716, 1197, 1346, 1474, 1654, 2912, 3415; HRMS (ESI-TOF) m/z calcd for C27H26N2O [M+H] 395.2123, found 395.2128. 6-Phenyl-1,5-di-p-tolyl-2,3,6,7- tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8k). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid p-tolylamide (1.0 mmol), benzaldehyde dimethyl acetal (2 mmol) and p-toluidine (1.0 mmol). Purification by the column chromatography (10% ethyl acetate-petroleum ether) afforded the title compound as yellow solid (300 mg, 0.76 mmol, 76% yield): mp 118-122 ᴼC; 1H NMR (300 MHz, CDCl3) δ 2.15 (3Η, s), 2.19 (3H, s), 2.71-2.93 (3H, m), 3.25-32 (1H, m), 3.77-3.87 (2H, m), 5.02-5.05 (1H, m), 6.65 (2H, d, J = 4.2 Hz), 6.91-7.13 (6H, m), 7.17 (5H, s); 13C NMR (75MHz, CDCl3) δ 14.2, 20.7, 20.9, 25.6, 32.3, 53.6, 62.5, 106.1, 119.6, 120.7, 125.6, 126.7, 127.4, 128.5, 129.1, 129.8, 133.1, 134.7, 140.0, 141.3, 153.1, 166.1; FT-IR (KBr, cm-1): 701, 1241, 1406, 1514, 1636, 2924, 3435; HRMS (ESI-TOF) m/z calcd for C27H26N2O [M+H] 395.2123, found 395.2119. 1-(4-Ethylphenyl)-6-phenyl-5-p-tolyl-2,3,6,7- tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8l). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid p-tolylamide (1.0 mmol), benzaldehyde dimethyl acetal (2 mmol) and p-ethyl aniline (1.0 mmol). Purification by the column chromatography (10% ethyl acetatepetroleum ether) afforded the title compound as light yellow solid (310 mg, 0.77 mmol, 77% yield): mp 128-132 ᴼC; 1H NMR (300 MHz, CDCl3) δ 1.17 (3Η, t, J = 8.1 Hz), 2.16 (3Η, s), 2.50 (2H, q, J = 7.5 Hz), 2.74-2.93 (3H, m), 3.27 (1H, dd, J = 6.6Hz, 16.5Hz), 3.78-3.88 (2H, m), 5.03-5.06 (1H, m), 6.68 (2H, d, J = 4.2 Hz), 6.92-7.03 (6H, m), 7.13-7.12 (5H, m); 13C NMR (75MHz, CDCl3) δ 15.2, 20.6, 25.4, 27.8, 32.1, 53.3, 62.2, 105.9, 120.4, 125.3, 126.5, 127.1, 128.2, 128.3, 128.8, 134.4, 139.1, 139.8, 141.1, 152.6, 165.7; FT-IR (KBr, cm-1): 693, 1248, 1383, 1405,1522, 1638, 3201; HRMS (ESI-TOF) m/z calcd for C28H28N2O [M+H] 409.2280, found 409.2285. 1-(4-Ethylphenyl)-6-(4-(hydroxymethyl)phenyl)-5-phenyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8m). The compound was prepared following the GP-III employing 1-acetyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), 4(hydroxymethyl)benzaldehyde dimethyl acetal (2.5 mmol) and p-ethyl aniline (1.0 mmol). Purification by the column chromatography (14% ethyl acetate-petroleum ether) afforded the title compound as white solid (318 mg, 0.75 mmol, 75%): mp 152-156 ᴼC; 1H NMR (300 MHz, CDCl3) δ 1.18 (3Η, t, J = 7.8 Hz), 2.07-2.13 (1H, m), 2.76-2.89 (2H, m), 3.66-3.71 (1H, m), 3.85-3.87 (1H, m), 4.02-4.12 (1H, m), 4.47- 4.66 (5H, m), 5.36 (1H, d, J = 2.1 Hz), 6.97 (2H, d, J = 4.1 Hz), 7.09-7.12 (1H, m), 7.12-7.52 (8H, m), 7.59 (1H, d, J = 3.9 Hz), 7.93 (1H, d, J = 3.5 Hz); 13C NMR (75MHz, CDCl3) δ 15.1, 26.9, 31.6, 51.8, 62.3, 104.2, 119.5, 120.4, 123.6, 124.5, 125.6, 125.7, 126.1, 127.5, 127.9, 128.9, 137.8, 138.2, 139.5, 140.3, 140.84, 142.3, 152.5, 164.2; FT-IR (KBr, cm-1): 712, 1264, 1328, 1480, 1653, 2936, 3276; HRMS (ESI-TOF) m/z calcd for C28H28N2O2 [M+H] 425.2229, found 425.2234. 1-(4-ethylphenyl)-2-methyl-5,6-diphenyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8n). The compound was prepared following the GP-III employing 1-acetyl-2-methyl-cyclopropanecarboxylic acid phenylamide (1.0 mmol), benzaldehyde dimethyl acetal (2 mmol) and p-ethyl aniline (1.0 mmol).. Purification by the column chromatography (12% ethyl acetate-petroleum ether) afforded the title compound as light brown solid (206 mg, 0.51 mmol, 51% yield); mp 77-79 ᴼC; 1H NMR (300 MHz, CDCl3) δ 1.18−1.24 (6Η, m), 2.52−2.67 (4Η, m), 3.08-3.16 (1H,m), 3.27-3.37 (1H, m), 4.19-4.34 (1H, m), 5.07-5.13 (1H, m), 6.00-6.78(2H,m), 7.03-7.07 (3H, m), 7.12-7.27 (9H, m); 13C NMR (75MHz, CDCl3) δ 15.3, 20.4, 28.2, 29.6, 31.9, 32.3, 34.2, 34.3,103.9, 124.2, 124.6, 124.8, 125.1, 126.5, 126.8, 127.2, 127.4, 128.2, 128.3, 128.4, 128.5, 128.6, 137.8, 137.9, 141.1, 141.4, 142.9, 153.7,165.8; FT-IR (KBr, cm-1): 713, 1198, 1448, 1472,1539, 1607, 3212; HRMS (ESITOF) m/z calcd for C28H29N2O [M+H] 409.2279, found 409.2276. Preparation of Cyclopropanes Acetoacetanilide Derivatives. To a stirred solution of acetoacetanilide (X, 10mmol) in dry DMF (20 mL), K2CO3 (2.76 g, 20 mmol) was added. 1,2-Dibromo ethane (Y, 14 mmol) was added after half an hour and stirred overnight under argon atmosphere at ambient temperature. After the reaction was over it was extracted with ethyl acetate (25 mL x 3) and washed with water (20 mLx3). Finally the combined organic layer was washed with brine (25 mL) and concentrated in a rotary evaporator under reduced pressure at room temperature. The crude product was purified by column chromatography (silica gel, 60-120 mesh) using ethyl acetate-petroleum ether as an eluent. Thus, the reaction of acetoacetanilide (1.77 g, 10 mmol) and 1,2-dibromo ethane (1.2 mL, 14 mmol) afforded corresponding 1-acetyl-Nphenylcyclopropanecarboxamide (1a)29 in 60% yield (1.21 g, 0.6 mmol).

18


Page 19 of 23

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


1-Benzoyl-N-(4-isopropylphenyl)cyclopropanecarboxamide (1c). Brown solid (1.94 gm, 5.4 mmol, 54% yield); mp 114116 ᴼC; 1H NMR (300 MHz, CDCl3) δ 1.18−1.27 (6Η,m), 1.50-1.51 (2H,m), 1.74-1.76 (2H,m), 2.82-2.86 (1H,m), 7.11(2H, d, J = 4.2Hz), 7.29-7.37(2H,m), 7.43-7.47(2H, m), 7.54 (1H, d, J= 2.4Hz), 7.96 (2H, d ,J = 3.6Hz), 8.22 (1H, s); 13C NMR (75 MHz,CDCl3): δ 10.1, 18.4, 27.8 , 30.4, 109.6,114.6, 120.7,121.4,123.0,127.6,130.6,131.0,132.7, 161.8,192.8. FT-IR (KBr, cm-1): 670, 754, 1286, 1346, 1412, 1440, 1530, 3264. HRMS (ESI-TOF) m/z calcd for C20H22N2O [M+H] 309.1684, found 309.1689. 1-Benzoyl-N-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-carboxamide (1g). Brown solid (1.90 gm, 5.2 mmol, 52% yield); mp 87-89 ᴼC; 1H NMR (300 MHz, DMSO-D6) δ 1.49−1.53 (2Η, m), 1.62-1.66 (2H, m), 7.43-7.54 (4H, m), 7.74-7.78 (1H,m), 7.90 (2H, d, J = 3.6Hz), 8.05 (1H, d, J= 1Hz), 11.35 (1H, s); 13C NMR (75 MHz, DMSOD6): δ 15.4, 36.9, 118.7, 121.2, 124.7, 124.8, 126.8, 127.2, 127.4, 128.5, 128.8, 132.1,133.1, 137.3, 138.6, 169.1, 195.8; FTIR KBr, cm-1): 630, 713, 1240, 1298, 1357, 1420, 1544, 3289; HRMS (ESI-TOF) m/z calcd for C18H14ClF3NO2 [M+H] 368.0665, found 368.0661. AUTHOR INFORMATION Corresponding Author Dilip K. Maiti Notes The authors declare no competing financial interests. ACKNOWLEDGMENT Fellowships from CSIR (SRF to SG and SD) and UGC (DSK-PDF to UKD), funding of SERB projects (No. SR/S5/GC-04/2012), Govt. of India, and instrument facilities of CRNN, CU are gratefully acknowledged.

Supporting Information Detailed nanofabrication procedure, SEM and TEM-EELS images and NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org. REFERENCES

(1) (a) Bruneau, C., Dixneuf, P. H. (Eds.), Topics in Organometallic Chemistry (Book 11): Ruthenium Catalysts and Fine Chemistry, Springer; 2004 edition (2004). (b) Rothenberg, G. Catalysis. Wiley, VHC, Weinheim, 2008. (c) Dong, G.; Teo, P.; Wickens, Z. K.; Grubbs, R. H. Primary alcohols from terminal olefins: formal anti-Markovnikov hydration via triple relay catalysis. Science 2011, 333, 1609. (d) Peplow, M. Catalysis: the accelerator. Nature 2013, 495, S10. (e) Laha, R. M.; Khamarui, S.; Manna, S. K.; Maiti, D. K. In situ generated Ag(II)-catalyzed selective oxo-esterification of alkyne with alcohol to α-ketoester: photophysical study. Org. Lett. 2016, 18, 144. (2) (a) Pacchioni, G. Nanocatalysis: staying put. Nature Mater. 2009, 8, 167. (b) Gellman, A. J.; Shukla, N. Nanocatalysis: More than speed. Nature Mater. 2009, 8, 87. (c) Polshettiwar, V.; Varma, R. S. Green chemistry by nano-catalysis. Green Chem. 2010, 12, 743. (d) Gayen, K. S.; Sengupta, T.; Saima, Y.; Das, A.; Maiti, D. K.; Mitra, A. Cu(0) nanoparticle catalyzed efficient reductive cleavage of isoxazoline, carbonyl azide and domino cyclization in water medium. Green Chem. 2012, 14, 1589. (e) Kundu, D.; Chatterjee, T.; Ranu, B. C. Magnetically separable CuFe2O4 nanoparticles catalyzed ligand-free C-S coupling in water: access to (E)- and (Z)-styrenyl-heteroaryl and sterically hindered aryl sulphides. Adv. Synth. Catal. 2013, 355, 2285. (f) Maity, S.; Eswaramoorthy, M. Ni–Pd bimetallic catalysts for the direct synthesis of H2O2 – unusual enhancement of Pd activity in the presence of Ni. J. Mater. Chem. A 2016, 4, 3233. (g) Roo, J. D.; Driessche, I. V.; Martins, J. C.; Hens, Z. Colloidal metal oxide nanocrystal catalysis by sustained chemically driven ligand displacement. Nature Mater. 2016, 15, 517. (3) (a) Somorjai, G. A.; Frei, H.; Park, J. Y. Advancing the frontiers in nanocatalysis, biointerfaces, and renewable energy conversion by innovations of surface techniques. J. Am. Chem. Soc. 2009, 131, 16589. (b) Mohamed, M. B.; Zeid, K. M. A.; Abdelsayed, V.; Aljarash, A. A.; El-Shall, M. S. Growth mechanism of anisotropic gold nanocrystals via microwave synthesis: formation of dioleamide by gold nanocatalysis. ACS Nano 2010, 4, 2766. (c) Snelders, D. J. M.; Yan, N.; Gan, W.; Laurenczy, G.; Dyson, P. J. Tuning the chemoselectivity of Rh nanoparticle catalysts by site-selective poisoning with phosphine ligands: The hydrogenation of functionalized aromatic compounds. ACS Catal. 2012, 2, 201. (d) Mahmoud, M. A.; Narayan, R.; El-Sayed, M. A. Enhancing colloidal metallic nanocatalysis: sharp edges and corners for solid nanoparticles and cage effect for hollow ones. Acc. Chem. Res. 2013, 46, 1795. (e) Cui, X.; Li, Y.; Bachmann, S.; Scalone, M.; Surkus, A.-E.; Junge, K.; Topf, C.; Beller, M. Synthesis and characterization of iron–nitrogen-doped graphene/core–shell catalysts: efficient oxidative dehydrogenation of N-heterocycles. J. Am. Chem. Soc. 2015,

19



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 20 of 23

137, 10652. (f) Walker, J. M.; Zaleski, J. M. A simple route to diverse noble metal-decorated iron oxide nanoparticles for catalysis. Nanoscale 2016, 8, 1535. (4) (a) Senra, J. D.; Viana, G. M.; Malta, L. F. B.; Simas, A. B. C.; Aguiar, L. C. S. Selectivity studies towards the synthesis of novel biaryl ureas by (hetero) nanocatalysis: Size control and support effects. ChemCatChem 2016, 8, 192. (b) Chen, T.; Chen, S.; Zhang, Y.; Qi, Y.; Zhao, Y.; Xu, W.; Zeng, J. Catalytic Kinetics of Different Types of Surface Atoms on Shaped Pd Nanocrystals. Angew. Chem. Int. Ed. 2016, 55, 1839. (5) (a) Chandra, P.; Doke, D. S.; Umbarkara, S. B.; Biradar, A. V. One-pot synthesis of ultrasmall MoO3 nanoparticles supported on SiO2, TiO2, and ZrO2 nanospheres: an efficient epoxidation catalyst. J. Mater. Chem. VI A, 2014, 2, 19060. (b) Khamarui, S.; Saima, Y.; Laha, R. M.; Ghosh, S.; Maiti, D. K. Functionalised Mn nanoparticles: an advanced high-valent magnetic catalyst. Sci. Rep. 2015, 5, 8636. (6) (a) Ahmad, T.; Ramanujachary, K. V.; Lofland, S. E.; Ganguli, A. K. Nanorods of manganese oxalate: a single source precursor to different manganese oxide nanoparticles (MnO, Mn2O3, Mn3O4). J. Mater. Chem. 2004, 14, 3406. (b) Samal, S. L.; Ramanujachary, K. V.; Lofland, S. E.; Govind; Ganguli, A. K. Stabilization of Mn (IV) in nanostructured zinc manganese oxide and their facile transformation from nanospheres to nanorods. J. Mater. Chem. 2011, 21, 8566. (7) (a) Hartwig, J. F. Carbon–heteroatom bond formation catalysed by organometallic complexes. Nature 2008, 455, 314. (b) Samanta, S.; Roy, D.; Khamarui, S.; Maiti, D. K. Ni(II)–salt catalyzed activation of primary 3 amine-sp Cα–H and cyclization with 1,2-diketone to tetrasubstituted imidazoles. Chem. Commun. 2014, 50, 2477. (8) (a) Ibrahim, A.; Hirschfeld, S.; Cohen, M. H.; Griebel, D. J.; Williams, G. A.; Pazdur, R. FDA drug approval summaries: oxaliplatin. Oncologist 2004, 9, 8. (b) Katsuyama, A.; Matsuda, A.; Ichikawa, S. Revisited mechanistic implications of the Joullié–Ugi three-component reaction. Org. Lett. 2016, 18, 2552. (9) (a) Zhao, J.; Clark, D. A. Regiodivergent synthesis of functionalized indene derivatives via Pt-catalyzed rautenstrauch reaction of propargyl carbonates. Org. Lett. 2012, 14, 1668. (b) Ghosh, S.; Khamarui, S.; IV Gayen, K. S.; Maiti, D. K. ArCH(OMe)2 - a Pt -catalyst originator for diverse annulation catalysis. Sci. Rep. 2013, 3, 2987. (c) Du, R.; Xiao, H.; Guo, G.; Jiang, B.; Yan, X.; Li, W.; Yang, X.; Zhang, Y.; Li, Y.; Jing, X. Nanoparticle delivery of photosensitive Pt(IV) drugs for circumventing cisplatin cellular pathway and ondemand drug release. Coll. Surf. B: Bioint. 2014, 123, 734. (d) Theiner, S.; Varbanov, H. P.; Galanski, M.; Egger, A. E.; Berger, W.; Heffeter, P.; Keppler, B. K. Comparative in vitro and in vivo pharmacological investigation of platinum(IV) complexes as novel anticancer drug candidates for oral application. J. Biol. Inorg. Chem. 2015, 20, 89. (10) (a) Daidouji, K.; Fuchibe, K.; Akiyama, T. Cu(I)-catalyzed enantioselective [3+2] cycloaddition reaction of 1alkylallenylsilane with α-imino ester: asymmetric synthesis of dehydroproline derivatives. Org. Lett. 2005, 7, 1051. (b) Fan, J.; Gao, L.; Wang, Z. Facile construction of highly functionalized 2-pyrrolines via FeCl3catalyzed reaction of aziridines with arylalkynes. Chem. Commun. 2009, 33, 5021. (c) Yang, J.; Zhou, X.; Zeng, Y.; Huang, C.; Xiao, Y.; Zhang, J. Synthesis of 2-fluoro-2-pyrrolines via tandem reaction of αtrifluoromethyl-α, β-unsaturated carbonyl compounds with N-tosylated 2-aminomalonates. Chem. Commun. 2016, 52, 4922. (11) (a) Hofmann, T.; Schieberle, P. 2-Oxopropanal, hydroxy-2-propanone, and 1-pyrroline important intermediates in the generation of the roast-smelling food flavor compounds 2-acetyl-1-pyrroline and 2acetyltetrahydropyridine. J. Agric. Food Chem. 1998, 46, 2270. (b) Borthakur, G.; O’Brien, S.; Ravandi, K. F.; Giles, F.; Schimmer. A. D.; Viallet, J.; Kantarjian. H. Dynamics of BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia (CML) after treatment with one, two or three tyrosine kinase inhibitors (TKI). Blood 2006, 108, 750. (c) Kaptein, A.; Oubrie, A.; de Zwart, E.; Hoogenboom, N.; de Wit, J.; van de Kar, B.; van Hoek, M.; Vogel, G.; de Kimpe, V.; Schultz-Fademrecht, C.; Borsboom, J.; van Zeeland, M.; Versteegh, J.; Kazemier, B.; de Roos, J.; Wijnands, F.; Dulos, J.; Jaeger, M.; Leandro-Garcia, P.; Barf, T. Discovery of selective and orally available spiro-3-piperidyl ATP-competitive MK2 inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 3823. (d) Zheng, X.; Bauer, P.; Baumeister, T.; Buckmelter, A. J.; Caligiuri, M.; Clodfelter, K. H.; Han, B.; Ho, Y. C.; Kley, N.; Lin, J.; Reynolds, D. J.; Sharma, G.; Smith, C. C.; Wang, Z.; Dragovich, P. S.; Gunzner, Toste .J.; Liederer, B. M.; Ly, J.; OÏBrien, T.; Oh A.; Wang, L.; Wang, W.; Xiao, Y.; Zak, M.; Zhao, G.; Yuen, P. W; Bair, K. W. Structure-based discovery of novel amide-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors. J. Med. Chem. 2013, 56, 6413. (e) Ershov, O. V.; Fedoseev, S. V.; Ievlev, M. Y.; Belikov, M. Y. 2-Pyridone-based fluorophores: Synthesis and fluorescent properties of pyrrolo [3, 4-c] pyridine derivatives. Dyes Pig. 2016, 134, 459. (f) Norkaew, O.; Boontakham, P.; Dumri, K.; Noenplab, A. N. L.; Sookwong, P.; Mahatheeranont, S. Effect of post-harvest treatment on bioactive phytochemicals of Thai black rice. Food Chem. 2017, 217, 98. (12) (a) Sakano, Y.; Shibuya, M.; Matsumoto, A.; Takahashi, Y.; Tomoda, H.; Ohmura, S.; Ebizuka, Y. Revised structures of epohelmins A and B isolated as lanosterol synthase inhibitors from a fungal strain FKI-0929. J. Antibiot. 2003, 56, 817. (b) Kiefl, J.; Pollner, G.; Schieberle, P. Sensomics analysis of key hazelnut odorants (Corylus avellana L.‘Tonda Gentile’) using comprehensive two-dimensional gas chromatography in combination with time-of-flight mass spectrometry (GC, GC-TOF-MS). J. Agric. Food Chem. 2013, 61, 5226. (c) Davidek, T.; Festring, D.; Dufossé, T.; Novotny, O.; Blank, I. Study to elucidate formation pathways of selected roast-smelling odorants upon extrusion cooking. J. Agric. Food Chem. 2013, 61, 10215. (13) (a) Butler, M. S. The role of natural product chemistry in drug discovery. J. Nat. Prod. 2004, 67, 2141. (b) Magedov, I. V.; Luchetti, G.; Evdokimov, N. M.; Manpadi, M.; Steelant, W. F. A.; Van Slambrouck, S.; Tongwa, P.; Antipin, M. Y.; Kornienko, A. Novel three-component synthesis and antiproliferative properties of diversely functionalized pyrrolines. Bioorg. Med. Chem. Let. 2008, 18, 1392. (c) Gupta, R.; Walunj, S. S.; To-

20


Page 21 of 23

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


kala, R. K.; Parsa, K. V; Singh, S. K.; Pal, M. Emerging drug candidates of dipeptidyl Peptidase IV (DPP IV) inhibitor class for the treatment of type 2 diabetes. Curr. Drug Targets 2009, 10, 71. (14) Patel, N.; Pera, P.; Joshi, P.; Dukh, M.; Tabaczynski, W. A.; Siters, K. E.; Kryman, M.; Cheruku, R. R.; Durrani, F.; Missert, J. R.; Watson, R.; Ohulchanskyy, T. Y.; Tracy, E. C.; Baumann, H.; Pandey, R. K. Highly effective dual-function near-infrared (NIR) photosensitizer for fluorescence imaging and photodynamic therapy (PDT) of cancer. J. Med. Chem. 2016, 59, 9774. (15) (a) Rivado-Casas, L.; Sampedro, D.; Campos, P. J.; Fusi, S.; Zanirato, V.; Olivucci, M. Fluorenylidene−pyrroline biomimetic light-driven molecular switches. J. Org. Chem. 2009, 74, 4666. (b) Morin, M. S. T.; Arndtsen, B. A. Chiral phosphorus-based 1,3-dipoles: a modular approach to enantioselective 1,3-dipolar cycloaddition and polycyclic 2-pyrroline synthesis. Org. Lett. 2014, 16, 1056. (c) Kang, Y. K.; Richers, M. T.; Sawicki, C. H.; Seidel, D. C–H functionalization of cyclic amines: redox-annulations with α, β-unsaturated carbonyl compounds. Chem. Commun. 2015, 51, 10648. (d) Nebe, M. M.; Kucukdisli, M.; Opatz, T. 3,4Dihydro-2 H-pyrrole-2-carbonitriles: useful intermediates in the synthesis of fused pyrroles and 2,2′bipyrroles J. Org. Chem. 2016, 81, 4112. (16) (a) Koehler, V.; Bailey, K. R.; Znabet, A.; Raftery, J.; Helliwell, M.; Turner, N. J. Enantioselective biocatalytic oxidative desymmetrization of substituted pyrrolidines. Angew. Chem. Int. Ed. 2010, 49, 2182. (b) Wisniewska, H. M.; Jarvo, E. R. Enantioselective silver-catalyzed propargylation of imines. Chem. Sci. 2011, 2, 807. (c) Wang, D.-S.; Ye, Z.-S.; Chen, Q.-A.; Zhou, Y.-G.; Yu, C.-B.; Fan, H.-J.; Duan, Y. Highly enantioselective partial hydrogenation of simple pyrroles: A facile access to chiral 1-pyrrolines. J. Am. Chem. Soc. 2011, 133, 8866. (d) Morin, M. S. T.; Arndtsen, B. A. Chiral phosphorus-based 1, 3-dipoles: A modular approach to enantioselective 1,3-dipolar cycloaddition and polycyclic 2-pyrroline synthesis. Org. Lett. 2014, 16, 1056. (e) Huang, H.; Yang, Q.; Zhang, Q.; Wu, J.; Liu, Y.; Song, C.; Chang, J. A Hofmann rearrangement–ring expansion cascade for the synthesis of 1-pyrrolines: application to the synthesis of 2,3-dihydro-1H-pyrrolo[2,1a]isoquinolinium salts. Adv. Synth. Catal. 2016, 358, 1130. (17) (a) Pandit, P.; Chatterjee, N.; Maiti, D. K. 1-Pyrrolines via intramolecular 1,3-dipolar cycloaddition of ketoimine: a complete diastereoselective approach. Chem. Commun. 2011, 47, 1285. (b) Mack, D. J.; Njardarson, J. T. Recent advances in the metal-catalyzed ring expansions of three-and four-membered rings. ACS Catal. 2013, 3, 272. (c) Shu, X.-z.; Zhang, M.; He, Y.; Frei, H.; Toste, F. D. Dual visible light photoredox and gold-catalyzed arylative ring expansion. J. Am. Chem. Soc. 2014, 136, 5844. (18) (a) Nitta, M.; Kobayashi, T. Novel type of transformations of α-azidostyrene derivatives and 3-aryl-2 Hazirines in the presence of hexacarbonylmolybdenum. Chem. Lett. 1983, 24, 1715. (b) Fan, X.; Zhang, Y. SmI2-mediated synthesis of 2,4-diarylpyrroles from phenacyl azides. Tetrahedron Lett. 2002, 43, 1863. (c) Hall, M. J.; McDonnell, S. O.; Killoran, J.; O’Shea, D. F. A modular synthesis of unsymmetrical tetraarylazadipyrromethenes. J. Org. Chem. 2005, 70, 5571. (d) Zhao, W.; Carreira, E. M. Conformationally restricted aza‐BODIPY: highly fluorescent, stable near‐infrared absorbing dyes. Chem. Eur. J. 2006, 12, 7254. (e) Thompson, B. B.; Montgomery, J. Org. Lett. 2011, 13, 3289. (f) Sakai, T.; Ito, S.; Furuta, H.; Kawahara, Y.; Mori, Y. Mechanism of the regi-and diastereoselective ring expansion reaction using trimethylsilyldiazomethane. Org. Lett. 2012, 14, 4564. (g) Sabbatani, J.; Maulide, N. Temporary generation of a cyclopropyl oxocarbenium ion enables highly diastereoselective donor–acceptor cyclopropane cycloaddition. Angew. Chem. Int. Ed. 2016, 55, 6780. (19) (a) Campos, P. J.; Sampedro, D.; Rodríguez, M. A. Photochemistry of imine−group VI carbene complexes with alkenes: synthetic scope and photochemical aspects Organomet. 2002, 21, 4076. (b) Sampedro, D.; Soldevilla, A.; Rodríguez, M. A.; Campos, P. J.; Olivucci, M. Mechanism of the N-cyclopropylimine-1pyrroline photorearrangement. J. Am. Chem. Soc. 2005, 127, 441. (c) Cui, B.; Ren, J.; Wang, Z. TfOHcatalyzed formal [3+ 2] cycloaddition of cyclopropane 1,1-diesters with nitriles. J. Org. Chem. 2014, 79, 790. (d) Martin, M. C.; Patil, D. V.; France, S. Functionalized 4-carboxy- and 4-keto-2,3-dihydropyrroles via Ni(II)catalyzed nucleophilic amine ring-opening cyclizations of cyclopropanes. J. Org. Chem. 2014, 79, 3030. (e) Zhang, Z.; Zhang, F.; Wang, H.; Wu, H.; Duan, X.; Liu, Q.; Liu, T.; Zhanga, G. Catalyst-free domino reaction of 1-acryloyl-1-N-arylcarbamylcyclopropanes with amines: one-pot approach to 2,3,6,7-tetrahydro-1Hpyrrolo[3,2-c]pyridin-4(5H)-ones. Adv. Synth. Catal. 2015, 357, 2681. (f) Miaskiewicz, S.; Weibel, J.-M.; Pale, P.; Blanc, A. Gold(I)-catalyzed cyclization/nucleophilic substitution of 1-(N-sulfonylazetidin-2-yl)ynones into N-sulfonylpyrrolin-4-ones. Org. Lett. 2016, 18, 844. (20) O’Regan, C.; Zhu, X.; Zhong, J.; Anand, U.; Lu, J.; Su, H.; Mirsaidov, U. CTAB-influenced electrochemical dissolution of silver dendrites. Langmuir 2016, 32, 3601. (21) Newbury, D. E.; Ritchie, N. W. M. Elemental mapping of microstructures by scanning electron microscopyenergy dispersive X-ray spectrometry (SEM-EDS): extraordinary advances with the silicon drift detector (SDD). J. Anal. At. Spectrom. 2013, 28, 973. (22) (a) Egerton, R. F. Electron energy-loss spectroscopy in the TEM. Rep. Prog. Phys. 2009, 72, 016502. (b) Wang, Z.; Santhanagopalan, D.; Zhang, W.; Wang, F.; Xin, H. L.; He, K.; Li, J.; Dudney, N.; Meng, Y. S. In situ STEM-EELS observation of nanoscale interfacial phenomena in all-solid-state batteries. Nano Lett. 2016, 16, 3760. (23) Wagner, C. D.; Riggs, W. M.; Davis, L. E.; Moulder, J. F.; Mullenberg, G. E. Handbook of X-ray Photoelectron Spectroscopy, Perkin-Elmer Corporation, Physical Electronics Division, Eden Prairie. MN 55344 (1979). (24) (a) Liang, F.; Lin, S.; Wei, Y. Aza-oxy-carbanion relay via non-brook rearrangement: efficient synthesis of furo[3,2-c]pyridinones. J. Am. Chem. Soc. 2011, 133, 1781. (b) Schneider, T. F.; Kaschel, J.; Werz, D. B. A new golden age for donor–acceptor cyclopropanes. Angew. Chem. Int. Ed. 2014, 126, 5504.

21



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 22 of 23

(25) (a) Hugi, A.; Villares, G.; Blaser, S.; Liu, H. C.; Faist, J. Mid-infrared frequency comb based on a quantum 3 cascade laser. Nature 2012, 492, 229. (b) Khamarui, S.; Maiti, R.; Maiti, D. K. Generation of transient λ hypervalent iodine, its reactivity, mechanism and broad application. RSC Adv. 2015, 5, 106633. (c) Das, T.; Debnath, S.; Maiti, R.; Maiti, D. K. Multifold C−C coupling and unorthodox cyclization catalysis for selective synthesis of indolotriarylmethanes, indolocarbazoles, and their analogues: a control experiment study. J. Org. Chem. 2017, 82, 688. (26) Singh, P.; Mittal, L. S.; Vanita, V.; Kumar, K.; Walia, A.; Bhargava, G.; Kumar, S. Self-assembled vesicle and rod-like aggregates of functionalized perylene diimide: reaction-based near-IR intracellular fluorescent probe for selective detection of palladium. J. Mat. Chem. B: Mat. Biol. Med. 2016, 4, 3750. (27) Balamurugan, R.; Chien, C. C.; Wu, K.2+M.; Chiu, Y. H.; Liu, J. H. A depropargylation-triggered fluorescence "Turn-On" probe for the detection of Pd based on a bispropargylamine-rhodamine conjugate. Analyst 2013, 138, 1564. (28) Rambabu, D.; Bhavani, S.; Swamy, N. K.; Rao, M.V. B.; Pal, M. Pd/C-mediated depropargylation of propargyl ethers/amines in water. Tetrahedron Lett. 2013, 54, 1169. (29) Bi, X.; Zhang, J.; Liu, Q.; Tan, J.; Li, B. Intramolecular aza-anti-Michael addition of an amide anion to enones: a regiospecific approach to tetramic acid derivatives. Adv. Synth. Catal. 2007, 349 2301.

22


Page 23 of 23

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


For Table of Contents Only

23


Fabrication and Diverse Ring-Expansion Nanocatalysis of

Recommend Documents