Sulfoximine-Assisted One-Pot Unsymmetrical Multiple Annulation of

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Sulfoximine Assisted One-Pot Unsymmetrical Multiple Annulation of Arenes: A Combined Experimental and Computational Study Koushik Ghosh, Majji Shankar, Raja Kumar Rit, GURUDUTT DUBEY, Prasad V. Bharatam, and Akhila Kumar Sahoo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01077 • Publication Date (Web): 31 Jul 2018 Downloaded from http://pubs.acs.org on July 31, 2018

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The Journal of Organic Chemistry

polycyclic compounds. Overall, three independent annulations in arene motifs are visualized and thoughtfully executed; finally, 5rings fused structural entities are constructed forming three CC and two CN bonds.

INTRODUCTION: Transition-metal (TM)-catalyzed direct annulation of CH bonds has had a tremendous impact in the field of chemistry. 1 This method has provided reliable pathways to synthesize complex molecular templates with diverse functionalities and has been utilized to generate potential pharmaceutical, agrochemical, and material candidates. 2 In this context, conventional multistep annulations of prefunctionalized substrates have proven to be feasible, however, most of these methods have clear disadvantages.3 For example, they suffer from lengthy multistep reactions, extensive separation procedures, and poor yields. In contrast, the directing group (DG)-assisted sequential annulation of multiple CH bonds is an attractive method as it can effectively afford asymmetrically fused heterocycles.4 However, demonstrations of multiple functionalization of CH bonds in a one-pot synthesis have unsurprisingly shown to be ineffective, because each step of the transformation yields several byproducts, reaction steps do not run to completion, and the steps lack selectivity. 5 Moreover, the unique selectivity of each catalytic system and DG for a particular functionalization is quite challenging. Nevertheless, a two-step protocol utilizing two different catalytic systems has recently been implemented for the synthesis of highly functionalized compounds (Figure 1a). 6 Although it is rarely investigated, the development of a one-pot domino/sequential two-fold CH functionalization process for the fabrication of unusual heterocycles has proven challenging and draws unparalleled attention. 7

Heterocycles, such as dihydrobenzofurans and isoquinolones are privileged molecular scaffold in organic synthesis due to their widespread presence in bioactive molecules and natural products. 8 Obviously, integration of both the representative heterocycle core (dihydrofuran and isoquinolone) builds a unique molecule with distinct feature. Realization of such heterocyclic scaffold is possible

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through a modifiable-DG aided functionalization of arenes by the sequential intramolecular hydroarylation of olefins and the intermolecular annulation of alkynes (Figure 1b). 9,10

In this context, the DG not only regulates the regioselective activation of CH bond but also ensures the formation of dihydrobenzofuran scaffold at first (via intramolecular hydroarylation of CHa bond) and then builds the isoquinolone [through annulation of CHb, alkyne, and transformable-DG (TfDG)] (Figure 1b). No such unsymmetrical diannulation transformation of arene under a single catalytic condition is so far devised, which obviously entices considerable interest.

Figure 1. Directing group assisted multiple CH functionalizations


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Herein, we present a one-pot, sequential, two-fold, asymmetrical CH annulation strategy of an MPSbearing m-O-allyl benzamide derivative, 1a. This reaction involves an intramolecular hydroarylation followed by intermolecular annulations of the benzamide product with an alkyne to yield a dihydrofuran-fused-isoquinolone framework (Figure 1c). The experimental and computational evaluation studies were utilized to address the inherent challenges and competitive pathways associated with the one-pot unsymmetrical diannulation of arene CH bonds. The unusual conjugated dihydrofuran-fused polycyclic amide skeleton is synthesized by a sequential or single-step multiple C–C and C–N bond formation processes. RESULTS AND DISCUSSION: To probe this hypothesis, a reaction of [3-(2-methylallyloxy)benzoyl]methylphenyl sulfoximine (1a) and diphenylacetylene (2a) under the catalytic conditions {[RuCl2(p-cymene)]2 (5.0 mol%), AgSbF6 (40 mol%), Cu(OAc)2·H2O (1.0 equiv) in 1,2-dichloroethane (ClCH2CH2Cl)} was at first performed at 25 oC for 24 h. To our disappointment, not even a trace of the envisioned desired product 4aa was detected; instead a 4:1 mixture of product 5a (annulation from sterically free o-site) and 5′a (annulation from sterically congested o-site) along with small amount of the hydroarylation product 3a (99% deuterium (D) incorporation into the sterically free o-CHb bond, while o-CHa underwent 60% D exchange (eq 1). Although both o-CH bonds are available to metalation, the steric hindrance of the O-allyl moiety likely inhibits the D-exchange of CHa. Surprisingly, a minor D incorporation into the CHa bond occurred when 1b was exposed to Ru-catalysis in the presence of 4octyne, while the CHb bond experienced 99% D incorporation (eq 2).11 This is possibly owing to the coordination of the alkyne to the Ru-catalyst prior to CH activation. Thus, the bulkiness of the preformed catalytic species is responsible for discriminating against the activation of the sterically hindered o-CH bond. As expected, the CHb activation was reversible, as the reaction of 3a under Rucatalysis in acetic acid-D4 yielded 48% D incorporation (eq 3).12 The annulation of 3a-H and 3a-D (1:1) under Ru-catalysis and Cu(OAc)2·H2O in DCE resulted in 77%-H scrambling of the CHb bond along with 12% 4ah (eq 4).


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Scheme 2: Deuterium scrambling experiments To support the formation of the observed products in Scheme 1 and the D-scrambling experiments in Scheme 2, three competitive reaction paths are proposed (Scheme 3). The activation of the sterically free o-CHb bond of arene 1a with Ru-catalyst forms the ruthenacycle I, which undergoes migratory insertion with alkynes followed by CN bond formation to give the annulation product 5 (path A, Scheme 3). Likewise, formation of ruthenacycle II is possible through the activation of sterically hindered o-CHa bond; alkyne insertion to the species II followed by the annulation finally leads to product 5' [path B-(i), Scheme 3]. Formation of the desired product 4 happens via hydroarylation with the tethered alkene followed by subsequent o-CHb activation and annulation with alkyne [path B-(ii), Scheme 3]. Despite the viable pathways detailed in Scheme 3, the facile intermolecular annulation over the intramolecular hydroarylation in Scheme 1 appears disagreeable. To understand this reaction dichotomy, further investigation is therefore necessary. ACS Paragon Plus Environment

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Scheme 3. Competitive pathways of multiple annulations. To gain insightful information’s in this one-pot two-fold CH functionalizations, which involves intramolecular hydroarylation and intermolecular annulation sequence (Scheme 1), we thus pursued examining the density functional theory (DFT) 13 calculations (using Gaussian09 software)14 of probable intermediates involved in the domain of this transformation. The DFT studies were performed using Becke’s three parameter hybrid density functional method (B3LYP) with LANL2DZ double zeta pseudo potential for Ru and 6-31+G(d,p) basis set for all other atoms. 15 This level of quantum chemistry was found to be suitable in explaining the bonding and reactivity at the Ru centre. 16 The potential energy diagram for the concerted metalation-deprotonation (CMD) process for the formation of ruthenacycles I and II is shown in Figure 2. The conformation analysis of substrate 1 resulted six possible conformers. The chosen conformer of 1 is the most stable conformer. Metal insertion to 1 yields the intermediate IN1, which is the most stable conformer among all four conformers of IN1 (see supporting information). Therefore, the catalytic cycle begins with the coordination of MPS-nitrogen of 1 with active Ru(II)-catalyst and forms the intermediate IN1 by releasing an energy of 2.1 kcal/mol. The CMD process by Ru-coordinated acetate provides regioisomers IN3 (CHb activated) and IN3′ (CHa activated). The loss of acetic acid yields five-membered o-ruthenated ACS Paragon Plus Environment

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species I via path A and II through path B (Scheme 3). The ruthenacycle I is more stable than the reactants by 1.3 kcal/mol and II is slightly less stable than the reactants by 0.4 kcal/mol.

Figure 2. Energy profile for concerted metalation-deprotonation (CMD) for the formation of ruthenacycles I and II (the 2D structures are shown for path A leading to I).17 The species I and II are thus involved in the annulations with alkynes to form the respective products 5 and 5′; the potential energy surfaces for these annulations are detailed in Figure 3.


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Figure 3. Energy profile for the formation of undesired products 5 and 5′ (Bond distances are in Å). The intermediates I and II undergo regioselective annulation after co-ordination with alkyne at the Ru-center. The barriers for the formation of intermediates III and IV respectively from I and II are 27.0 and 26.5 kcal/mol. The inclusion of acetic acid to the Ru-alkyne inserted species III and IV (supported by hydrogen bonding with the carbonyl moiety) results the intermediates IN5 and IN5′ with the demand of 4.2 and 3.7 kcal/mol, respectively. Alternative geometries of IN5 and IN5′ were also considered. One, in which acetic acid interacts directly with the Ru-center and second, in which two molecules of acetic acid can be taken into account for proton transfer. In all the alternative geometries, the transition state could not be identified on the respective potential energy surfaces. The appropriate transition states can be achieved only when one molecule of acetic acid (hydrogen bonded with the carbonyl moiety) is considered.


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On Path A, the energy difference between turnover determining intermediate I and turnover determining transition state TS3 leads to the energy span of 25.7 kcal/mol for the formation of 5. Similarly, the energy span due to II and TS3′ is 31.6 kcal/mol for the formation of 5′ on path B(i). Thus, energy span is in favor of path A leading to formation of 5 in major amount. The TS3 and TS3′ represent three processes, (i) CN bond formation, (ii) breaking of NS bond, and (iii) insertion of acetic acid to Ru-species. The overall energy released during the formation of product 5 and 5′ is 69.0 and 62.3 kcal/mol, respectively (Figure 3); thus, path A is facile (kinetic as well thermodynamic parameters) over path B. Accordingly, formation of annulation products 5 and 5′ (Scheme 1A) is corroborated by the DFT studies. To further gain insights into the practicability of the envisioned process in path B(ii), Scheme 3, the potential energy surface of the catalytic cycle for the intramolecular hydroarylation and intermolecular annulation sequence is studied (Figure 4). The allyl ether moiety undergoes rotational transformation and coherently inserts to the five-membered o-ruthenated species II (see: path B in Figure 2 and Figure 4) to form the seven-membered boat shaped ruthenacycle V via TS2″ [path B(ii) in Scheme 3]; the energy barrier demands 15.7 kcal/mol from II to attain V. Next, the insertion of acetic acid to V forms the intermediate IN4″ with endothermicity of 3.0 kcal/mol. The proto-demetalation followed by rotational transformation of IN4″ results the intermediate IN5″ (stabilized by 11.8 kcal/mol). Finally, expulsion of the active Ru-catalyst from IN5″ yields dihydrobenzofuran 3, which is more stable than II by 8.7 kcal/mol, reflecting the feasibility of the intramolecular hydroarylation process. At the same time, the IN5″ can possibly involve the CMD process to afford IN6″ through insertion of Ru at CHb position. The loss of acetic acid from the IN6″ yields VI; the process is exothermic by 2.4 kcal/mol. Migratory alkyne co-ordination to Ru in VI forms IN7″; concurrently, stabilization of IN7″ leads to seven-membered boat shaped ruthenacycle VII (releasing 14.6 kcal/mol). Acetic acid insertion to VII results IN8″ (less stable by 3.9 kcal/mol). The energy barrier demands 30.0 kcal/mol to attain transition state TS3″, which is probably responsible for the construction of CN bond. The energy ACS Paragon Plus Environment

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barriers seems high at the particular steps of C bond formation. Since the experiment was carried out at 90 oC, the energy required to cross this barrier is probably compensated.

2.06 2.18

2.14

2.24

2.25

7.95

1.66 2.15

2.11

1.03 1.48 IN7ʹʹ

IN8ʹʹ

IN9ʹʹ

Figure 4. Energy profile for the formation of desired dihydrofuran-fused-isoquinolone 4 through sequential addition of alkyne (Bond distances are in Å).


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Acetic acid plays a crucial role in CN bond formation. Thus, acetic acid assisted elimination of methylphenyl sulfoxide drives the formation of CN bond in a concerted manner. Hydrogen shift from acetic acid to the carbonyl of MPS-amide leads to iminol system IN9″; this possibly occurs via an eightmembered cyclic species combining MPS-N, Ru, and the acetic acid. The concomitant detachment of methylphenyl sulfoxide constructs the CN bond. Finally, the dihydrofuran-fused isoquinolinol undergoes tautomerization to yield the desired product 4 from IN9″ with exothermicity of 7.9 kcal/mol. Based on the quantum chemical calculations, the formation of dihydrofuran-fused isoquinolone 4 is thermodynamically more favorable over 5 and 5′ by 10.9 and 17.6 kcal/mol, respectively. In this context, products 5 and 5′ are kinetically favorable, while 4 is thermodynamically most viable. As both intramolecular hydroarylation and intermolecular annulations are energetically favorable, a complex outcome was thereby observed when the reaction was performed in a single-operation. The overall results from Schemes 12 and Figures 24 conveyed that the one-pot unsymmetrical functionalization of CH bonds with distinct functional groups is non-selective, uncontrolled and thus unproductive. Accordingly, development of synthetic methods for unsymmetrical functionalization of multiple CH bonds is a worthwhile endeavour. To address the challenges of one-pot divergent annulations, a synthetic method comprising of intramolecular hydroarylation with olefin followed by intermolecular annulation with alkyne was planned under the single catalytic conditions. As the MPSDG assisted intramolecular hydroarylation of arenes occurred at RT under the Ru-catalysis, the subsequent addition of alkyne to the reaction mixture and then performing the annulations at an elevated temperature was consequently envisioned. Hence, the reaction between 1a and 2a under the Rucatalysis was performed to obtain the designed dihydrofuran-fused-isoquinolone scaffold. The optimization details were shown in Table 1. To start with, 1a was exposed to the catalytic conditions comprising of {[RuCl2(p-cymeme)]2 (5.0 mol %), AgSbF6 (40 mol %), Cu(OAc)2.H2O (1.0 equiv)} in 1,2-dichloroethane (ClCH2CH2Cl) at rt for 4 h, subsequently 2a was introduced and the resulting mixture was heated at 100 °C for 12 h; this process ACS Paragon Plus Environment

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provided the desired compound 4aa in 59% yield (entry 1, Table 1). Screening of various bases [NaOAc, KOAc, Mn(OAc)2] and Ag-salts (AgBF4, AgPF6) were found inferior (entries 27). Performing the reaction in 1,4-dioxane/HFIP produced moderate amount of 4aa (entries 8 and 9). Improved yield of 4aa (69%) was perceived when slight excess of catalyst (6.5 mol %) was employed (entry 10); the use of Ru-catalyst (7.5 mol %) did not substantially enhance the product outcome (entry 11). The reaction in presence of less amount AgSbF6 (30 mol %) was equally effective (entry 12). Finally, the reaction of 1a under the catalyst system {[RuCl2(p-cymene)]2 (6.5 mol %), AgSbF6 (30 mol %), Cu(OAc)2·H2O (1.0 equiv) in 1,2-DCE} at rt for 2 h followed by the addition of 2a and heating at 100 oC for 8 h led to 4aa (fused heteroaryl scaffold) in 74% yield (entry 13). Table 1. Optimization of the Reaction Conditionsa

yield (%)

additive

base

(40 mol %)

(1.0 equiv)

1

AgSbF6

Cu(OAc)2·H2O ClCH2CH2Cl 59

2

AgSbF6

Cu(OAc)2

ClCH2CH2Cl 54

3

AgSbF6

NaOAc

ClCH2CH2Cl 11

4

AgSbF6

KOAc

ClCH2CH2Cl ~10

5

AgSbF6

Mn(OAc)2

ClCH2CH2Cl 37

6

AgBF4


7

AgPF6


8

AgSbF6

Cu(OAc)2·H2O 1,4-dioxane

49

9

AgSbF6

Cu(OAc)2·H2O HFIP

29

10c

AgSbF6


11d

AgSbF6


12e

AgSbF6


entry

solvent

of 4aab


13

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13f

AgSbF6

Cu(OAc)2.H2O ClCH2CH2Cl 74

a

Reaction conditions: 1a (0.1 mmol), [RuCl2(p-cymeme)]2 (5.0 mol %), Ag-salt (40 mol %), base/oxidant (1.0 equiv), solvent (1.0 mL) at rt for 2 h; then 2a (0.11 mmol) was introduced and heated at 120 °C for 10 h. bConversion based on crude 1 H NMR. cRu-cat (6.5 mol %). dRu-cat (7.5 mol %). e Ru-cat (6.5 mol %), AgSbF6 (30 mol %). fReaction was stirred at rt for 2 h then 2a was added; the resulting mixture heated at 100 C for 8 h under the identical conditions of e. The synthetic generality of this recently crafted one pot two-fold unsymmetrical intramolecularhydroarylation and intermolecular-annulation of O-allyl-tethered MPS-bearing N-aroyl carboxylate derivatives with alkynes is validated by constructing wide range of dihydrofuran-fused-isoquinolone scaffolds through multiple cyclization of C(sp2)H bonds of arenes (Scheme 4 and 5). The compound 4aa was isolated in 77% yield from 1a and 2a. The precursors 1be having electron donating and withdrawing substituent at 4-position in the arene-motif reacted smoothly with 2a to produce 4baea in good to excellent yield; the NO2 Scheme 4. Double Annulation of Arenes with 1,2-Diphenylacetylene


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and fluoro (F) functional groups did not affect the productivity. Substitution at 5-position (Me/Cl) in arene, which makes ‘o′’ sterically congested for second annulation, did not hamper the reactivity delivering the respective products 4faha. To note, the labile O-benzyl group was survived under the catalytic conditions. Pleasingly, 4ia (49%) was isolated from the challenging annulations of the electron-rich and the ‘o/o′’ sterically encumbered 4,5-dimethoxy substituted 1i with 2a. The unsubstituted allyl-ether moiety smoothly underwent tandem hydroarylation-annulation, affording 4ja (68%), and 4ka (59%). Scheme 5. Double Annulation of Arenes with 1,2-Di(hetero)arylacetylenes


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The modified tethered alkenes were participated in the annulations; for instance, several 1,1 and 1,2disubstiuted alkene bearing arenes were successfully participated hydroarylation and annulation sequence to yield the desired product 4laand 4ma in appreciable yields. The challenging internal trisubstituted olefin was not an exception, delivering 4na in 66% yield. The scope of alkynes (2bm) was next surveyed pursuing the reliability of this one-pot hydroarylation-annulation process; the results are summarized in Scheme 5. Annulation of the electron rich 1,2-diaryl acetylenes having para-substitution on arene moiety [tBu (2b), OMe (2c), and Me (2d)] with 1a/1b afforded the corresponding dihydrofuran-fused isoquinolones 4ab (75%), 4ac (62%), 4bb (79%), and 4bd (77%). The challenging dialkyl alkyne (i.e. 4-octyne, 2h) smoothly participated in the annulation, constructing 4ah in appreciable yields. The product 4bl (40%) was isolated from the hydroarylation-annulation sequence of 1b with 1,2-bis(2-thienyl)ethyne (2l). The alkynes [having ACS Paragon Plus Environment

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para/meta/ortho-substituted arene moiety]/4-octyne annulated effectively with 1d under the optimized conditions accessing 4de (81%), 4dg (58%), 4di (63%), 4dj (54%), and 4dh (85%); the modifiable Brgroup was survived. The product 4dk was isolated from the reaction of 1d with 2k (m,p-dichloro arene bearing alkyne). To further authenticate the synthetic viability of this two-fold annulation, the reaction among the challenging unsubstituted m-O-allyl-ether containing MPS-coupled carboxylate and 1f/1i/1h was independently performed; the respective products 4jf, 4ji, and 4kh were isolated albeit in moderate yield. The dihydrofuran-fused-isoquinolone 4jm was exclusively produced (confirmed by NOESY studies) from the reaction of 1j with alkyl-aryl alkyne 2m; the aryl--electron interaction with Ruspecies helps the formation of 4jm. The results detailed in Scheme 5 truly demonstrates the reaction generality exhibiting broad alkyne scope. Scheme 6. Annulation of Dihydrofurano-isoquinolone with 1,2-Diarylacetylenes

Polycyclic amide motifs are often found in molecules of biological and material importance, which eventually attracted immense attention.17 With our recent observation, we wondered that the free NH and the proximal arene C(sp2)H bond of the dihydrofuran-fused-isoquinolone 4 can further participate ACS Paragon Plus Environment

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in the annulation with alkynes (Scheme 6). 18 With this intention, the annulation between 4 and 2 was conducted in the presence of base-mediated Ru-catalysis (Scheme 6). An extended dihydrofuran-fused polycyclic amides 6aab (70%) was isolated from 4aa and 2b by erecting a CC and CN bond. Likewise, the extended -conjugated dihydrofuran-fused polycyclic amides 6aaf (66%) was fabricated from annulation of 4aa with 2f. The dialkyl alkyne (i.e. 4-octyne, 2h) annulated successfully with 4aa to result 6aah. As expected, the reaction among 4aa and unsymmetrical alkyne (2n) gave mixture of the respective products 6aan. The desired product 6nae (67%) was resulted from the reaction between 4na and 2e. We believe the current synthetic manifestation is unique, as five-ring-fused skeletons are readily constructed from the commercially available 3-hydroxy-benzoic acid derivatives involving an intramolecular hydroarylation and two intermolecular annulations with different alkynes. We then envisaged probing the sequential hydroarylation-diannulation transformations in one-pot under single catalytic system;19 as this method would directly build five (3-CC and 2-CN) bonds by activating environmentally dissimilar CH bonds, which is obviously challenging and is unknown. To our surprise, reaction between 1a and 2a under Ru-Ag-Cu combination directly provided five-ring fused heteroaryl amides 6aaa. Similarly, 6aff and 6baa were fabricated from the annulation of {1a with 2f} and {1b with 2a}, respectively in one-pot. Noteworthy to mention that the current process functionalizes environmentally three different CH bonds forming 3-CC and 2-CN bonds in one-pot under singly catalytic conditions (Scheme 7). Scheme 7. One Pot Three-fold CH Functionalization


18


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On the basis of observed facts (Scheme 1 and 2) and DFT studies, the probable mechanistic cycle is deduced (Figure 2, 3, 4). The reaction initiates with the coordination of active catalyst [Ru(pcymene)(OAc)]+, obtained in-situ from [Ru(p-cymene)Cl2]2 in presence of AgSbF6 & Cu(OAc)2, with MPS. Acetate assisted proton removal of proximal o-CH bond of arene then generates five membered metallacycle II′, which is possibly stabilized by the tethered alkene. The CC bond formation through alkene insertion and migration of Ru-species gives intermediate V.

Figure 5. Mechanistic Cycle.


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Next, AcOH mediated proto-demetallation delivers dihydrobezofuran skeleton;7a the simultaneous acetate incorporation to the Ru generates active catalyst and coordinates to the N-of sulfoximine. Then, CC (arene and carbonyl) bond rotation and activation of o′-CH bond of arene with the removal of AcOH affords cyclometalation complex VI. Alkyne insertion to VI and carboruthanation to alkyne produces seven-membered Ru-species VII. The acetic acid promoted expulsion of phenyl methyl sulfoxide finally provides metal coordinated iminol intermediate IN10′′, which further undergo amideiminol tautomerization to deliver the desired furano-isoquinolone 4 with the generation of active catalyst (Figure 5). Conclusions: We herein revealed a novel synthetic paradigm for the design and development of dihydrofuran-fused-isoquinolone

skeleton

by

combining

intramolecular

hydroarylation

and

intermolecular annulation strategies from readily accessible aryl carboxylic acids in a single operation. This one-pot two-fold unsymmetrical annulation of arene CH bonds is successfully executed under the assistance of MPS-DG in Ru-catalysis and wide range of unusual dihydrofuran-fused-isoquinolones even with the modifiable functional groups on the periphery are fabricated. The computed DFT studies authenticated the kinetically feasible intermolecular annulation and the formation of thermodynamically stable dihydrofuran-fused-isoquinolone; the sequence of annulations is accordingly devised and reliably experimented. Furthermore, three independent modes of annulations in arene motifs are effected constructing highly conjugated 3/5 rings-fused unique polycyclic compounds with the formation of three CC and two CN bonds in one-pot. Experimental Section General Information: All the reactions were performed in an oven-dried Schlenk flask. Commercial grade solvents were distilled prior to use. Column chromatography was performed using either 100200 Mesh or 230400 Mesh silica gel. Thin layer chromatography (TLC) was performed on silica gel GF254 plates. Visualization of spots on TLC plate was accomplished with UV light (254 nm) and staining over I2 chamber.


20


Proton, carbon, and fluorine nuclear magnetic resonance spectra ( 1H NMR,

Page 20 of 42 13

C NMR and

were recorded based on the resonating frequencies as follows: (1H NMR, 400 MHz;

13

19

F NMR)

C NMR, 101

MHz; 19F NMR, 376 MHz) and (1H NMR, 500 MHz; 13C NMR, 126 MHz; 19F NMR, 470 MHz) having the solvent resonance as internal standard ( 1H NMR, CDCl3 at 7.26 ppm;

13

C NMR, CDCl3 at 77.0

ppm). Few cases tetramethylsilane (TMS) at 0.00 ppm was used as reference standard. Data for 1H NMR are reported as follows: chemical shift (ppm), multiplicity (s  singlet; bs  broad singlet; d  doublet; bd  broad doublet, t  triplet; bt  broad triplet; q  quartet; m  multiplet), coupling constants, J, in (Hz), and integration. Data for

13

C NMR, 19F NMR were reported in terms of chemical

shift (ppm). IR spectra were reported in cm1. Elemental (C, H, N) analysis were carried out using FLASH EA 1112 analyzer. Melting points were determined by electro-thermal heating and are uncorrected. High resolution mass spectra were obtained in ESI mode in Maxis-TOF analyzer. Melting points were determined by electro-thermal heating and are uncorrected. X-ray data was collected at 298 K using graphite monochromated Mo-K radiation (0.71073 Å). Materials: Unless otherwise noted, all the reagents and intermediates were obtained commercially and used without purification. Dichloromethane (DCM), 1,2-dichloroethane (DCE), and chloroform were distilled over CaH2. THF was freshly distilled over sodium/benzophenone ketyl under dry nitrogen. [Ru(p-cymene)Cl2]2, AgSbF6, AgBF4, KPF6 were purchased from Sigma Aldrich Ltd, and used as received. Bases such as Cu(OAc)2.H2O, KOAc, NaOAc, AgOAc were purchased from Aldrich Ltd. and used as received. Analytical and spectral data of all those known compounds are exactly matching with the reported values. Preparation of N-aroyl sulfoximine derivatives (1); General Procedure (GP-1): Following the known procedure, the desired N-aroylsulfoximine derivatives were prepared from the corresponding benzoic acids in excellent yield (8095%) and used for the reaction.7a,9e the compounds 1f, 1g, 1k, 1l are synthesized for the first time (details are available in Supporting information).


21

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N-[3-Methyl-5-((2-methylallyl)oxy)benzoyl]-S-methyl-S-phenylsulfoximine

(1f).

Following

the

general procedure GP-1, compound 1f was obtained 88% yield as colorless solid; m.p.  128130 C; Rf  0.34 (7:3 hexane/EtOAc); 1H NMR (500 MHz, CDCl3) 8.03 (d, J  8.0 Hz, 2H), 7.67 (t, J  7.2 Hz, 1H), 7.637.57 (m, 3H), 7.50 (bs, 1H), 6.90 (bs, 1H), 5.09 (s, 1H), 4.98 (s, 1H), 4.44 (s, 2H), 3.44 (s, 3H), 2.35 (s, 3H), 1.81 (s, 3H);

13

C NMR (125 MHz, CDCl3) 174.1, 158.5, 140.7, 139.0, 136.7,

133.7, 129.6, 127.0, 122.8, 120.1, 112.6, 111.9, 71.7, 44.2, 21.3, 19.3; IR (Neat) max 3054, 2923, 1628, 1591, 1449, 1327, 1228, 1157, 1119, 1051 cm1; HRMS (ESI) for C19H22NO3S (M+H)+: calcd. 344.1320, found 344.1318. N-[3-Chloro-5-((2-methylallyl)oxy)benzoyl]-S-methyl-S-phenylsulfoximine (1g).

Following

the

general procedure GP-1, compound 1g was obtained 85% yield as colorless solid; m.p.  134137 C; Rf  0.35 (7:3 hexane/EtOAc); 1H NMR (500 MHz, CDCl3) 8.02 (d, J  7.0 Hz, 2H), 7.74 (bs, 1H), 7.68 (bt, J  8.2 Hz, 1H), 7.61 (bt, J  7.2 Hz, 2H), 7.57 (bs, 1H), 7.05 (bs, 1H), 5.07 (s, 1H), 4.98 (s, 1H), 4.43 (s, 2H), 3.44 (s, 3H), 1.80 (s, 3H); 13C NMR (125 MHz, CDCl3) 172.6, 159.1, 140.1, 138.5, 138.0, 134.4, 133.9, 129.7, 127.0, 122.0, 119.1, 113.5, 113.1, 72.0, 44.3, 19.3; IR (Neat) max 3065, 2925, 1627, 1591, 1449, 1327, 1305, 1229, 1120, 1052 cm1; HRMS (ESI) for C18H19ClNO3S (M+H)+: calcd. 364.0774, found 364.0773. N-[3-(Allyloxy)-4-methylbenzoyl]-S-methyl-S-phenylsulfoximine (1k):

Following the general

procedure GP-1, compound 1k was obtained 84% yield as colorless solid; m.p.  85 C; Rf  0.43 (7:3 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 8.05 (d, J  7.6 Hz, 2H), 7.73 (dd, J  7.6, 1.6 Hz, 1H), 7.68 (bt, J  7.4 Hz, 1H), 7.647.57 (m, 3H), 7.17 (d, J  Hz, 1H), 6.146.01 (m, 1H), 5.43 (dd, J  17.2, 1.6 Hz, 1H), 5.27 (dd, J  10.6, 1.4 Hz, 1H), 4.59 (dt, J  4.8, 1.6 Hz, 2H), 3.46 (s, 3H), 2.29 (s, 3H);

13

C NMR (101 MHz, CDCl3) 174.2, 156.4, 139.2, 134.4, 133.7, 133.4, 131.9, 130.1,

129.6, 127.1, 122.1, 117.0, 111.6, 68.7, 44.3, 16.5; IR (Neat) max 3065, 3018, 2920, 1625, 1576, 1501,


22


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1448, 1410, 1266, 1224, 1121, 1021 cm1 ; HRMS (ESI) for C18H20NO3S (M+H)+: calcd. 330.1164, found 330.1158. N-[3-((2-(Methoxymethyl)allyl)oxy)-4-methylbenzoyl]-S-methyl-S-phenylsulfoximine

(1l).

Following the general procedure GP-1, compound 1l was obtained 77% yield as colorless solid; Rf  0.23 (7:3 hexane/EtOAc); 1H NMR (500 MHz, CDCl3) 8.068.01 (m, 2H), 7.72 (dd, J  8.0, 1.5 Hz, 1H), 7.67 (tt, J  7.5, 1.8 Hz, 1H), 7.637.57 (m, 3H), 7.17 (d, J  7.5 Hz, 1H), 5.36 (s, 1H), 5.26 (s, 1H), 4.58 (s, 2H), 4.03 (s, 2H), 3.45 (s, 3H), 3.34 (s, 3H), 2.29 (s, 3H);

13

C NMR (101 MHz, CDCl3)

174.1, 156.4, 141.5, 139.2, 134.5, 133.7, 131.8, 130.1, 129.6, 127.1, 122.1, 114.3, 111.5, 73.3, 68.5, 58.0, 44.3, 16.5; IR (Neat) max 3065, 2925, 1717, 1626, 1576, 1502, 1449, 1409, 1289, 1223, 1115 cm1; HRMS (ESI) for C20H24NO4S (M+H)+: calcd. 374.1426, found 374.1424. General Procedure for the Unsymmetrical Two-fold CH Functionalization (Intramolecular Hydroarylation & Intermolecular annulation) Reaction (GP-2): The two-fold CH functionalization reactions were conducted in a 50 mL Schlenk tube having high pressure valve and side arm. The tube was charged with (1, 0.25 mmol), [Ru(p-cymene)Cl2]2 (10.0 mg, 6.5 mol %), and Cu(OAc)2·H2O (50.0 mg, 0.25 mmol). Subsequently, the additive AgSbF6 (26.0 mg, 0.075 mmol) was introduced to the flask in a glove box. 1,2-Dichloroethene (DCE; 2.0 mL) was added to the mixture and the resulting mixture was stirred at room temperature for 2 h followed by the addition of alkyne (2, 0.30 mmol); the resulting mixture was then heated at 95100 oC for 810 h. The reaction mixture was filtered through a plug of Celite and washed with dichloromethane (3 × 5.0 mL). The solvents were evaporated under the reduced pressure and the crude material was purified using column chromatography on silica gel (100% n-hexane/EtOAc eluent) to give the desired product. 9,9-Dimethyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one

(4aa).7a Following

the

general procedure GP-2, compound 4aa (71 mg, 77%) was obtained as colorless crystalline solid; m.p.  350 C; Rf  0.50 (7:3 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 9.50 (bs, 1H), 7.317.11 (m, ACS Paragon Plus Environment

23

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11H), 7.06 (d, J  8.8 Hz, 1H), 4.32 (s, 2H), 1.57 (s, 6H); 13C NMR (101 MHz, CDCl3)  161.5, 159.5, 136.7, 135.3, 134.5, 134.4, 134.3, 131.9 (2C), 129.2 (2C), 128.32 (3C), 128.29 (2C), 128.2, 127.5, 127.1, 117.6, 116.2, 86.4, 44.6, 26.7 (2C); IR (Neat) max 3117, 3090, 1638, 1594, 1561, 1468, 1336, 1183 cm1; HRMS (ESI) for C25H22NO2 (M+H)+: calcd. 368.1651, found 368.1651. 6,9,9-Trimethyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4ba). Following the general procedure GP-2, compound 4ba (69 mg, 73%) was obtained as colorless crystalline solid; m.p. >360 C; Rf  0.48 (8:2 hexane/EtOAc); 1H NMR (400 MHz, DMSO-d6) 11.21 (bs, 1H), 7.327.22 (m, 3H), 7.19 (bs, 5H), 7.11 (d, J  6.4 Hz, 2H), 6.79 (bs, 1H), 4.32 (bs, 2H), 2.11 (s, 3H), 1.60 (s, 6H); 13

C NMR (101 MHz, CDCl3) 160.9, 157.8, 137.3, 136.1, 135.2, 134.5, 133.3, 132.3, 130.2, 128.7,

128.3, 128.1, 127.4, 127.1, 126.4, 121.7, 116.1, 85.7, 44.9, 27.1, 16.4; IR (KBr) max 2863, 1634, 1469, 1433, 1381, 1340, 1081, 1035 cm1; HRMS (ESI) for C26H24NO2 (M+H)+: calcd. 382.1807, found 382.1803. 6-Methoxy-9,9-dimethyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one

(4ca).

Following the general procedure GP-2, compound 4ca (70 mg, 70%) was obtained as colorless crystalline solid; m.p.  351354 C; Rf  0.33 (8:2 hexane/EtOAc); 1H NMR (400 MHz, DMSO-d6)

11.02 (bs, 1H), 7.347.24 (m, 3H), 7.21 (bs, 5H), 7.16 (d, J  6.8 Hz, 2H), 6.51 (s, 1H), 4.33 (s, 2H), 3.56 (s, 3H), 1.62 (s, 6H); 13C NMR (101 MHz, DMSO-d6) 160.5, 148.6, 148.5, 137.3, 137.0, 136.3, 135.3, 135.2, 132.2, 130.2, 128.7, 128.3, 128.1, 127.5, 117.0, 116.1,107.1, 86.2, 55.5, 45.2, 27.0; IR (Neat) max 2920, 1634, 1593, 1453, 1417, 1293, 1216, 1174, 1097 cm1; HRMS (ESI) for C26H24NO3: (M+H)+: calcd. 398.1756, found 398.1754. 6-Fluoro-9,9-dimethyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4da). Following the general procedure GP-2, compound 4da (80 mg, 83%) was obtained as colorless crystalline solid; m.p. > 365 C; Rf  0.54 (8:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 9.86 (bs, 1H), 7.337.27 (m, 3H), 7.257.18 (m, 5H), 7.147.09 (m, 2H), 6.91 (d, J  9.6 Hz, 1H), 4.41 (s, 2H), 1.54 (s, 6H); 13C ACS Paragon Plus Environment

24


Page 24 of 42

NMR (101 MHz, CDCl3) 161.0, 151.1 (d, J  254 Hz), 147.1 (d, J  12 Hz), 138.7 (d, J  4.0 Hz), 136.3, 136.2, 135.8, 135.0, 131.8, 129.2, 129.1, 128.5, 128.39, 128.36, 127.4, 117.1 (d, J  3.0 Hz), 112.4 (d, J  18 Hz), 87.6, 45.5, 26.5;

19

F NMR (376 Hz): 129.1; IR (KBr) max 2915, 2848, 1737,

1639, 1603, 1489, 1417, 1334, 1257 cm1 ; HRMS (ESI) for C25H21FNO2 (M+H)+: calcd. 386.1556, found 386.1554. 9,9-Dimethyl-6-nitro-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4ea). Following the general procedure GP-2, compound 4ea (66 mg, 64%) was obtained as brown crystalline solid; m.p. >365 C; Rf  0.30 (8:2 hexane/EtOAc); 1H NMR (400 MHz, DMSO-d6 + CDCl3)  (bs, 1H), 7.67 (s, 1H), 7.377.27 (m, 3H), 7.23 (bs, 5H), 7.207.15 (m, 2H), 4.54 (s, 2H), 1.65 (s, 6H); 13C NMR (101 MHz, DMSO-d6) 160.0, 152.4, 140.9, 138.2, 136.1, 136.0, 134.5, 134.0, 132.2, 130.2, 129.0, 128.8, 128.2, 128.0, 127.1, 122.1, 115.7, 87.6, 44.8, 26.4; IR (Neat) max 3168, 2915, 1644, 1520, 1438, 1329, 1236, 1035 cm1; HRMS (ESI) for C25H20N2NaO4: (M+Na)+: calcd. 435.1321, found 435.1314. 5,9,9-Trimethyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4fa). Following the general procedure GP-2, compound 4fa (38 mg, 40%) was obtained as colorless crystalline solid; m.p.  354357 C; Rf  0.67 (8:2 hexane/EtOAc); 1H NMR (400 MHz, THF-d8) 10.50 (bs, 1H), 7.167.11 (m, 5H), 7.117.07 (m, 3H), 7.077.03 (m, 2H), 6.87 (s, 1H), 4.23 (s, 2H), 1.70 (s, 3H), 1.62 (s, 6H); 13

C NMR (101 MHz, CDCl3) 160.7, 159.2, 146.5, 140.4, 136.6, 136.5, 132.24, 132.18, 132.1, 129.8,

127.4, 127.24, 127.22, 126.2, 125.4, 119.4, 115.7, 85.9, 45.1, 25.9, 24.8; IR (Neat) max 2941, 1643, 1587, 1448, 1364, 1092, 1024 cm1; HRMS (ESI) for C26H24NO2 (M+H)+: calcd. 382.1807, found 382.1807. 5-Chloro-9,9-dimethyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4ga). Following the general procedure GP-2, compound 4ga (61 mg, 61%) was obtained as colorless crystalline solid; m.p.  350352 C; Rf  0.58 (8:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 10.59 (bs, 1H), 7.227.17 (m, 3H), 7.16 (s, 1H), 7.157.07 (m, 5H), 7.056.98 (m, 2H), 4.24 (s, 2H), 1.37 (s, 6H); 13C ACS Paragon Plus Environment

25

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NMR (101 MHz, CDCl3) 161.1, 159.2, 138.2, 137.1, 137.0, 135.3, 134.4, 132.1, 131.6, 130.1, 129.5, 128.0, 127.2, 126.5, 125.4, 119.8, 115.8, 86.6, 45.1, 26.2; IR (KBr) max 3044, 2951, 2920, 1639, 1577, 1437, 1370, 1241, 1122 cm1; HRMS (ESI) for C25H21ClNO2 (M+H)+: calcd. 402.1261, found 402.1255. 5-(Benzyloxy)-9,9-dimethyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one

(4ha).

Following the general procedure GP-2, compound 4ha (48 mg, 42%) was obtained as colorless crystalline solid; m.p.  349352 C; Rf  0.46 (8:2 hexane/EtOAc); 1H NMR (400 MHz, DMSO-d6)

11.18 (bs, 1H), 7.227.10 (m, 6H), 7.107.03 (m, 2H), 7.006.94 (m, 2H), 6.936.79 (m, 6H), 4.64 (s, 2H), 4.25 (s, 2H), 1.57 (s, 6H);

13

C NMR (101 MHz, DMSO-d6) 160.5, 159.8, 156.4, 140.6, 136.5,

136.4, 135.8, 131.2, 130.4, 128.4, 127.9, 127.83, 127.79, 127.7, 126.8, 125.7, 125.5, 125.1, 123.6, 114.4, 100.9, 86.0, 70.6, 44.8, 27.3; IR (KBr) max 2920, 2848, 1644, 1593, 1448, 1329, 1293, 1076 cm1; HRMS (ESI) for C32H28NO3 (M+H)+: calcd. 474.2069, found 474.2067. 5,6-Dimethoxy-9,9-dimethyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one

(4ia):

Following the general procedure GP-2, compound 4ia (52 mg, 49%) was obtained as colorless crystalline solid; Rf  0.32 (3:2 hexane/EtOAc); 1 H NMR (400 MHz, CDCl3)  8.94 (bs, 1H), 7.207.14 (m, 3H), 7.147.05 (m, 7H), 4.36 (s, 2H), 3.97 (s, 3H), 3.07 (s, 3H), 1.61 (s, 6H); 13C NMR (101 MHz, CDCl3) 160.3, 152.2, 148.8, 142.5, 140.3, 137.7, 131.6, 131.5, 130.42, 130.37, 128.5, 128.0, 127.8, 126.8, 125.8, 119.3, 113.8, 86.4, 60.7, 60.5, 45.2, 26.8; IR (KBr) max 3073, 2925, 1634, 1587, 1433, 1102, 1071 cm1; HRMS (ESI) for C27H25NNaO4 (M+Na)+: calcd. 450.1681, found 450.1676. 9-Methyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4ja):7a Following the general procedure GP-2, compound 4ja (60 mg, 68%) was obtained as colorless crystalline solid; m.p. = 320321 C; Rf  0.80 (7:3 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 10.03 (bs, 1H), 7.377.23 (m, 8H), 7.227.15 (m, 3H), 7.09 (d, J  8.8 Hz, 1H), 4.64 (t, J  8.4 Hz, 1H), 4.43 (dd, J  8.6, 2.0 Hz, 1H), 4.264.14 (m, 1H), 1.36(d, J  6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) 162.3, 158.7, 136.5, ACS Paragon Plus Environment

26


Page 26 of 42

135.3, 134.6, 133.6, 132.1, 131.9, 131.8, 129.4 (2C), 128.3, 128.2, 128.1 (3C), 127.1, 126.8, 122.1, 117.6, 115.6, 79.7, 37.6, 21.3; IR (Neat) max 2914, 2882, 1643, 1572, 1457, 1254, 1084 cm1 ; HRMS (ESI) for C24H20NO2 (M+H)+: calcd. 354.1494, found 354.1493. 6,9-Dimethyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one

(4ka).

Following

the

general procedure GP-2, compound 4ka (54 mg, 59%) was obtained as colorless crystalline solid; m.p.  204208 C; Rf  0.25; 1H NMR (400 MHz, CDCl3 + DMSO-d6) 9.97 bs, 1H), 7.207.04 (m, 10H), 6.84 (bs, 1H), 4.52 (bt, J  8.4 Hz, 1H), 4.354.29 (m, 1H), 4.134.06 (m, 1H), 2.12 (s, 3H), 1.25 (d, J  6.8 Hz, 3H);

13

C NMR (101 MHz, CDCl3 + DMSO-d6) 161.9, 157.2, 136.5, 135.2, 134.5, 133.4,

131.7, 131.6, 130.8, 129.2, 128.0, 127.8, 126.8, 126.6, 126.4, 120.0, 117.0, 79.3, 37.6, 21.1, 15.8; IR (Neat) max 2928, 1638, 1443, 1355, 1293, 1152 cm1; HRMS (ESI) for C25H22NO2 (M+H)+: calcd. 368.1651, found 368.1650. 9-(Methoxymethyl)-6,9-dimethyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4la). Following the general procedure GP-2, compound 4la (76 mg, 74%) was obtained as colorless crystalline solid; m.p.  285288 C; Rf  0.37 (8:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 9.44 (bs, 1H), 7.317.27 (m, 3H), 7.247.17 (m, 5H), 7.157.11 (m, 2H), 6.99 (d, J  0.4 Hz, 1H), 4.74 (d, J  6.8 Hz, 1H), 4.27 (d, J  6.8 Hz, 1H), 4.05 (bd, J  6.8 Hz, 1H), 3.67 (d, J  6.8 Hz, 1H), 3.30 (s, 3H), 2.19 (s, 3H), 1.53 (s, 3H);

13

C NMR (101 MHz, CDCl3)  161.5, 159.3, 136.8, 135.4, 134.4, 134.3,

131.9, 129.3, 129.2, 128.3, 128.2, 128.14, 128.12, 127.3, 127.1, 121.4, 117.5, 82.3, 77.7, 59.3, 49.6, 23.2, 16.2; IR (KBr) max 3158, 2920, 1629, 1433, 1329, 1293, 1190, 1107, 1076 cm1; HRMS (ESI) for C27H26NO3 (M+H)+: calcd. 412.1913, found 412.1911. 9-Ethyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4ma). Following the general procedure GP-2, compound 4ma (64 mg, 70%) was obtained as colorless crystalline solid; m.p.  290293 C; Rf  0.42 (8:2 hexane/EtOAc); 1 H NMR (400 MHz, DMSO-d6)  11.27 (bs, 1H), 7.327.22 (m, 3H), 7.20 (bs, 5H), 7.177.09 (m, 3H), 6.94 (d, J  8.4 Hz, 1H), 4.574.51 (m, 2H), 4.134.05 (m, 1H), 1.921.82 (m, 1H), 1.621.51 (m, 1H), 0.88 (t, J  7.4 Hz, 3H);

13

C NMR (101


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MHz, DMSO-d6)  161.5, 158.8, 137.0, 136.1, 135.3, 133.5, 132.19, 132.16, 130.4, 130.3, 128.7, 128.6, 128.3, 128.1, 127.4, 126.6, 122.8, 116.3, 115.5, 76.5, 43.9, 27.6, 11.4; IR (KBr) max 3018, 2920, 2858, 1639, 1593, 1484, 1345, 1247, 1148 cm1; HRMS (ESI) for C25H22NO2 (M+H)+: calcd. 368.1651, found 368.1656. 9-Ethyl-9-methyl-3,4-diphenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4na): Following the general procedure GP-2, compound 4na (63 mg, 66%) was obtained as colorless crystalline solid; m.p.  330333 C; Rf  0.51; 1H NMR (400 MHz, CDCl3)  9.78 (bs, 1H), 7.337.27 (m, 3H), 7.24 (bs, 5H), 7.237.13 (m, 3H), 7.06 (d, J  8.8 Hz, 1H), 4.49 (d, J  8.4 Hz, 1H), 4.25 (d, J  8.8 Hz, 1H), 2.392.29 (m, 1H), 1.641.56 (m, 1H), 1.54 (s, 3H), 0.74 (t, J  7.4 Hz, 3H);

13

C NMR (101 MHz,

CDCl3)  160.2, 136.8, 135.2, 134.4, 132.2, 131.9, 129.2, 129.1, 128.33, 128.27, 128.25, 128.16, 127.5, 127.1, 117.6, 116.0, 115.9, 83.5, 48.7, 31.3, 26.2, 9.6; IR (KBr) max 3158, 2920, 1649, 1598, 1463, 1329, 1272, 1247 cm1; HRMS (ESI) for C26H24NO2 (M+H)+: calcd. 382.1807, found 382.1807. 3,4-Bis(4-(tert-butyl)phenyl)-9,9-dimethyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one

(4ab).

Following the general procedure GP-2, compound 4ab (90 mg, 75%) was obtained as colorless crystalline solid; Rf  0.57 (8:2 hexane/EtOAc); m.p = 331334 oC; 1H NMR (500 MHz, THF-d8)

10.48 (bs, 1H), 7.33 (d, J  8.5 Hz, 2H), 7.26 (d, J  8.5 Hz, 2H), 7.16 (d, J  8.5 Hz, 3H), 7.08 (d, J  8.0 Hz, 2H), 7.01 (d, J  9.0 Hz, 1H), 4.31 (s, 2H), 1.67 (s, 6H), 1.33 (s, 9H), 1.27 (s, 9H); 13C NMR (125 MHz, THF-d8) 159.3, 150.4, 149.4, 135.5, 134.7, 134.55, 134.47, 133.8, 133.0, 132.5, 131.6, 129.2, 127.0, 124.7, 124.3, 115.9, 115.1, 86.0, 44.5, 34.14, 34.12, 30.7, 30.5, 26.2; IR (KBr) max 2961, 1638, 1465, 1263, 1100, 1084 cm1; HRMS (ESI) for C33H38NO2 (M+H)+: calcd. 480.2903, found 480.2907. 3,4-Bis(4-methoxyphenyl)-9,9-dimethyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one

(4ac).

Following the general procedure GP-2, compound 4ac (66 mg, 62%) was obtained as colorless crystalline solid. m.p.  358361 C; Rf  0.35 (8:2 hexane/EtOAc); 1H NMR (500 MHz, CDCl3) 9.81 (bs, 1H), 7.18 (d, J  8.5 Hz, 1H), 7.167.11 (m, 2H), 7.077.02 (m, 3H), 6.866.81 (m, 2H), 6.776.73 ACS Paragon Plus Environment

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(m, 2H), 4.30 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 1.54 (s, 6H);

13

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C NMR (101 MHz, CDCl3)  161.6,

159.22, 159.16, 158.5, 135.0, 134.4, 134.1, 132.9, 130.4, 129.0, 127.7, 127.3, 122.9, 116.8, 116.1, 113.8, 113.7, 86.4, 55.2, 44.6, 26.7; IR (KBr) max 3059, 2951, 2920, 1634, 1505, 1458, 1329, 1241, 1179, 1004 cm1; HRMS (ESI) for C27H26NO4 (M+H)+: calcd. 428.1862, found 428.1861. 9,9-Dimethyl-3,4-dipropyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one

(4ah).

Following

the

general procedure GP-2, compound 4ah (61 mg, 82%) was obtained as colorless crystalline solid; m. p.  212214 C; Rf  0.68 (8:2 hexane/EtOAc). 1H NMR (400 MHz, CDCl3) 11.95 (bs, 1H), 7.57 (d, J  9.2 Hz, 1H), 7.21 (d, J  8.8 Hz, 1H), 4.33 (s, 2H), 2.69 (q, J  8.0 Hz, 4H), 1.831.72 (m, 2H), 1.71 (s, 6H), 1.681.53 (m, 2H), 1.04 (t, J  7.4 Hz, 6H); 13C NMR (125 MHz, CDCl3) 162.8, 158.4, 135.5, 134.3, 134.0, 124.4, 123.2, 116.1, 113.0, 86.2, 44.8, 32.4, 29.3, 26.9, 23.5, 23.0, 14.3, 13.9; IR (Neat)

max 2951, 2868, 1644, 1463, 1355, 1267, 1128, 1004 cm1 ; HRMS (ESI) for C19H26NO2 (M+H)+: calcd. 300.1964, found 300.1966. 3,4-Bis(4-(tert-butyl)phenyl)-6,9,9-trimethyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one

(4bb).

Following the general procedure GP-2, compound 4bb (97 mg, 79%) was obtained as colorless crystalline solid; m.p.  C; Rf  0.68 (8:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 8.91 (s, 1H), 7.28 (d, J  8.4 Hz, 2H), 7.18 (d, J  8.0 Hz, 2H), 7.087.02 (m, 5H), 4.34 (s, 2H), 2.22 (s, 3H), 1.63 (s, 6H), 1.32 (s, 9H), 1.25 (s, 9H);

13

C NMR (101 MHz, CDCl3) 161.2, 158.2, 151.0, 149.9,

134.8, 134.3, 133.9, 133.3, 132.6, 131.5, 128.6, 127.7, 127.1, 125.0, 121.1, 117.1, 86.3, 44.9, 34.53, 34.51, 31.3, 31.1, 26.9, 16.1;IR (Neat) max 2951, 1634, 1453, 1324, 1200, 1107, 885 cm1; HRMS (ESI) for C34H40NO2 (M+H)+: calcd. 494.3059, found 494.3059. 6,9,9-Trimethyl-3,4-di-p-tolyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4bd). Following the general procedure GP-2, compound 4bd (79 mg, 77%) was obtained as colorless crystalline solid; 0.079 g, 77% yield as colorless solid. m.p. = 318321 C; Rf  0.58 (8:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 9.38 (bs, 1H), 7.137.05 (m, 4H), 7.056.99 (m, 4H), 6.98 (s, 1H), 4.32 (s, 2H), 2.35 (s, 3H), ACS Paragon Plus Environment

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2.29 (s, 3H), 2.20 (s, 3H), 1.56 (s, 6H); 13C NMR (101 MHz, CDCl3) 161.5, 158.1, 137.7, 136.5, 134.9, 134.5, 133.9, 133.2, 132.7, 131.7, 129.0, 127.5, 127.0, 121.0, 117.0, 86.2, 44.8, 26.8, 21.3, 21.2, 16.1; IR (KBr) max 3287, 3152, 2920, 1644, 1515, 1543, 1257 cm1 ; HRMS (ESI) for C28H28NO2 (M+H)+: calcd. 410.2120, found 410.2124. 6,9,9-Trimethyl-3,4-di(thiophen-2-yl)-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one

(4bl).

Following the general procedure GP-2, compound 4bl (39 mg, 40%) was obtained as colorless crystalline solid; Rf  0.42 (3:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 9.76 (bs, 1H), 7.50 (dd, J = 4.4, 0.8 Hz, 1H), 7.327.26 (m, 2H), 7.17 (dd, J  4.4, 2.8 Hz, 1H), 7.05 (s, 1H), 7.04 (dd, J  2.8, 0.8 Hz, 1H), 7.026.97 (m, 1H), 4.35 (s, 2H), 2.25 (s, 3H), 1.61 (s, 6H);

13

C NMR (101 MHz, CDCl3) 

161.3, 158.7, 137.3, 136.3, 135.1, 133.4, 130.8, 130.4, 128.2, 127.74, 127.70, 127.5, 127.4, 127.1, 126.7, 120.9, 109.2, 86.3, 44.8, 26.7, 16.2; IR (Neat) max 3152, 2961, 1639, 1433, 1252, 1061, 694 cm1; HRMS (ESI) for C22H20NO2S2 (M+H)+: calcd. 394.0935, found 394.0932. 6-Fluoro-3,4-bis(4-fluorophenyl)-9,9-dimethyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4de). Following the general procedure GP-2, compound 4de (86 mg, 81%) was obtained as colorless crystalline solid; Rf  0.44 (8:2 hexane/EtOAc); m. p. > 350 oC ; 1H NMR (500 MHz, DMSO-d6)

11.50 (bs, 1H), 7.297.22 (m, 2H), 7.217.12 (m, 4H), 7.127.04 (m, 2H), 6.70 (d, J  15.5 Hz, 1H), 4.44 (s, 2H), 1.62 (s, 6H); 13C NMR (125 MHz, DMSO-d6) 162.1 (J 247 Hz), 161.7 (J  245 Hz), 160.3, 150.4 (J  252 Hz), 146.5 (J  12.1 Hz), 139.2 (J  4.0 Hz), 137.1, 135.9 (J  7.1 Hz), 134.1 (J  8.1 Hz), 132.8 (J  4.0 Hz), 132.5 (J  9.1 Hz), 131.2 (J  3.0 Hz), 120.1, 115.8 (J  21 Hz), 115.2 (J  22 Hz), 114.9 (J  2.0 Hz), 111.7 (J  18 Hz), 87.1, 45.6, 26.6; F19 NMR (126 MHz, CDCl3)  129.89, 114.65, 113.13; IR (Neat) max 3152, 2956, 2920, 1634, 1505, 1448, 1334, 1216, 1154, 1086 cm1; HRMS (ESI) for C25H19F3NO2 (M+H)+: calcd. 422.1368, found 422.1369. 6-Fluoro-9,9-dimethyl-3,4-bis(4-(trifluoromethyl)phenyl)-8,9-dihydrofuro[2,3-h]isoquinolin1(2H)-one (4dg). Following the general procedure GP-2, compound 4dg (75 mg, 59%) was obtained as ACS Paragon Plus Environment

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colorless crystalline solid; m.p. C Rf  0.68 (8:2 hexane/EtOAc); 1H NMR (500 MHz, DMSO-d6)

11.66 (bs, 1H),7.67 (d, J  8.0 Hz, 2H), 7.61 (d, J  8.0 Hz, 2H), 7.45 (m, J  8.0 Hz, 2H), 7.41 (d, J  7.5 Hz, 2H), 6.67 (d, J  12 Hz, 1H), 4.46 (s, 2H), 1.63 (s, 6H); 13C NMR (125 MHz, CDCl3)  157.8, 149.1, 147.1, 144.5, 144.4, 138.4, 137.02, 137.00, 136.2, 134.3, 132.7, 132.6, 130.7, 128.8, 127.1, 126.8, 126.6, 126.5, 126.2, 126.0, 125.7, 123.39, 123.36, 123.25, 123.1, 122.70, 122.68, 121.1, 120.9, 117.9, 112.6, 109.4, 109.3, 84.8, 43.2, 24.2; 19F NMR (376 MHz, CdCl3): 61.02, 61.21, 129.57; IR (Neat) max 2920, 1639, 1613, 1453, 1319, 1164 cm1 ; HRMS (ESI) for C27H19F7NO2 (M+H)+: calcd. 522.1304, found 522.1303. 6-Fluoro-9,9-dimethyl-3,4-dipropyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4dh). Following the general procedure GP-2, compound 4dh (68 mg, 85%) was obtained as colorless crystalline solid; m.p.  257 C; Rf  0.60 (8:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 12.00 (s, 1H), 7.29 (s, 1H), 4.43 (s, 2H), 2.68 (t, J  7.8 Hz, 2H), 2.62 (t, J  8.0 Hz, 2H), 1.821.72 (m, 2H), 1.71 (bs, 6H), 1.651.52 (m, 2H), 1.080.99 (m, 6H); 13C NMR (101 MHz, CDCl3) 162.2, 151.3 (d, J = 253.3 Hz), 146.1 (d, J  12.1 Hz), 138.4 (d, J  4 Hz), 137.0, 136.1 (d, J  8.1 Hz), 119.3, 112.6 (d, J  4.0 Hz), 109.5 (d, J  17.2 Hz), 87.4, 45.8, 32.4, 29.4, 26.7, 23.3, 23.0, 14.3, 13.9; IR (KBr) max 3168, 2956, 2930, 1644, 1500, 1453, 1340, 1272, 1164, 1045 cm1 ; HRMS (ESI) for C19H25FNO2 (M+H)+: calcd. 318.1869, found 318.1866. 6-Fluoro-9,9-dimethyl-3,4-di-m-tolyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4di). Following the general procedure GP-2, compound 4di (65 mg, 63%) was obtained as colorless crystalline solid; m.p.  288291 C. Rf  0.59 (8:2 hexane/EtOAc); 1H NMR (500 MHz, CDCl3) 11.14 (bs, 1H),7.16 (t, J  7.7 Hz, 1H), 7.126.98 (m, 5H), 6.956.87 (m, 3H), 4.36 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.38 (s, 6H); 13C NMR (101 MHz, CDCl3)  161.4, 151.0 (d, J  253.3 Hz), 146.9 (d, J  11.3 Hz), 138.4 (d, J  3.8 Hz), 137.8, 137.6, 136.4 (d, J  7.6 Hz), 136.2, 134.7, 132.3, 130.0, 129.0, 128.7, 128.2, 127.99, 127.96, 126.5, 119.1, 117.3 (d, J = 2.5 Hz), 112.3 (d, J = 17.6 Hz), 87.5, 45.4, 26.4, 21.3; 19F NMR (376 ACS Paragon Plus Environment

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MHz, CdCl3): 129.24; IR (Neat) max 3158, 2920, 1644, 1598, 1453, 1334, 1169, 1086 cm1; HRMS (ESI) for C27H25FNO2 (M+H)+: calcd. 414.1869, found 414.1875. 3,4-Bis(2-bromophenyl)-6-fluoro-9,9-dimethyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4dj). Following the general procedure GP-2, compound 4dj (73 mg, 54%) was obtained as colorless crystalline solid; Rf  0.48 (8:2 hexane/EtOAc); m. p.  347350 oC; 1H NMR (400 MHz, DMSO-d6)

11.65 (bs, 1H), 7.697.58 (m, 2H), 7.347.17 (m, 6H), 6.44 (d, J  11.6 Hz, 1H), 4.46 (s, 2H), 1.64 (s, 3H), 1.62 (s, 3H); 13C NMR (101 MHz, DMSO-d6) 160.1, 150.6 (J = 252.5 Hz), 146.9 (J  12.1 Hz), 139.4 (J  4.0 Hz), 137.0, 136.8, 135.7, 134.6 (J  7.1 Hz), 133.0, 132.7, 132.3, 131.3, 130.6, 130.5, 128.5, 127.8, 126.1, 123.8, 120.3, 115.5 (J  2.0 Hz), 111.3 (J  18.2 Hz), 87.1, 45.7, 26.7, 26.6;

19

F

NMR (126 MHz, CDCl3)  130.05; IR (KBr) max 2956, 2919, 1653, 1506, 1453, 1339, 1192, 1024 cm1; HRMS (ESI) for C25H19Br2FNO2 (M+H)+: calcd. 541.9767, found 541.9766. 3,4-Bis(2,4-dichlorophenyl)-6-fluoro-9,9-dimethyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4dk). Following the general procedure GP-2, compound 4dk (80 mg, 61%) was obtained as colorless crystalline solid; Rf  0.53 (8:2 hexane/EtOAc); m. p. > 360 oC ; 1H NMR (400 MHz, CDCl3) 11.63 (s, 1H), 7.647.57 (m, 2H), 7.577.50 (m, 2H), 7.227.15 (m, 2H), 6.75 (d, J  9.6 Hz, 1H), 4.45 (s, 2H), 1.62 (s, 6H); 13C NMR (101 MHz, CDCl3)  160.1, 150.5 (d, J  252.0 Hz), 146.9 (d, J  11.3 Hz), 139.4, 137.0, 135.8, 135.1 (d, J  7.6 Hz), 134.9, 134.0, 132.55, 132.46, 131.7, 131.6, 131.2, 131.0, 130.9, 130.6, 130.5, 120.3 (d, J  1.3 Hz), 114.1 (d, J  2.5 Hz), 111.9 (d, J  17.6 Hz), 87.2, 45.6, 26.7, 26.6;

19

F NMR (126 MHz, CDCl3)  129.43; IR (Neat) max 2879, 1639, 1608, 1448, 1329, 1293,

1128, 1092 cm1; HRMS (ESI) for C25H16Cl4 FNNaO2 (M+Na)+: calcd. 543.9817, found 543.9817. 3,4-Bis(4-chlorophenyl)-9-methyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4jf).7a Following the general procedure GP-2, compound 4jf (64 mg, 61%) was obtained as colorless crystalline solid; m.p. > 300 C; Rf  0.50 (7:3 hexane/EtOAc); 1H NMR (400 MHz, DMSO-D6)  11.42 (bs, 1H), 7.37 (bd, J  9.6 Hz, 2H), 7.31 (d, J  8.4 Hz, 2H), 7.22 (d, J  8.8 Hz, 2H), 7.217.13 (m, 3H), 6.92 (d, J  ACS Paragon Plus Environment

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8.8 Hz, 1H), 4.60 (t, J  8.4 Hz, 1H), 4.39 (dd, J  8.6, 2.2 Hz, 1H), 4.19 (bt, J  6.6 Hz, 1H) 1.32 (d, J  6.8 Hz, 3H);

13

C NMR (101 MHz, CDCl3)  161.5, 158.7, 135.7, 135.3, 134.0 (2C), 133.9, 133.3,

133.0, 132.4, 132.3, 132.2 (2C), 128.9 (2C), 128.3 (2C), 126.5, 122.7, 115.9, 115.4, 79.4, 37.4, 21.7; IR (KBr) max 3671, 2914, 1643, 1484, 1397, 1353, 1249, 1150, 1084 cm1 ; MS(EI) m/z (%) 422 (M+, 100); 391 (11); Anal. Calcd for C24H17Cl2NO2: C, 68.26; H, 4.06; N, 3.32. Found: C, 68.15; H, 4.10; N, 3.38. 9-Methyl-3,4-di-m-tolyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4ji). Following the general procedure GP-2, compound 4ji (52 mg, 54%) was obtained as colorless crystalline solid; 0.052 g, 54% yield as colorless solid. m.p.  241244 C. Rf  0.34 (8:2 hexane/EtOAc); 1H NMR (500 MHz, DMSO-d6) 11.24 (bs, 1H),7.17 (td, J  7.5, 3.0 Hz, 1H), 7.13 (d, J  8.5 Hz, 1H), 7.117.00 (m, 4H), 7.006.87 (m, 4H), 4.59 (t, J  8.5 Hz, 1H), 4.38 (dd, J  8.7, 2.2 Hz, 1H), 4.244.15 (m, 1H), 2.22 (s, 3H), 2.19 (s, 3H), 1.32 (d, J  7.0 Hz, 3H);

13

C NMR (125 MHz, DMSO-d6)  161.5, 158.3, 137.6,

137.1, 137.0, 136.0, 135.1, 133.6, 132.7, 132.0, 130.9, 129.9, 129.2, 128.9, 128.5, 128.0, 127.9, 127.4, 126.7, 122.6, 116.3, 79.3, 37.4, 21.7, 21.42, 21.36; IR (Neat) max 2922, 2879, 1642, 1593, 1480, 1351, 1077 cm1; HRMS (ESI) for C26H24NO2 (M+H)+: calcd. 382.1807, found 382.1810. 6,9-Dimethyl-3,4-dipropyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one

(4kh).

Following

the

general procedure GP-2, compound 4kh (53 mg, 71%) was obtained as colorless crystalline solid; m. p. = 232234 C; Rf  0.63 (8:2 hexane/EtOAc). 1H NMR (400 MHz, CDCl3) 10.90 (bs, 1H), 7.29 (s, 1H), 4.60 (t, J  8.4 Hz, 1H), 4.41 (dd, J  8.4, 2.0 Hz, 1H), 4.314.23 (m, 1H), 2.692.57 (m, 4H), 2.37 (s, 3H), 1.791.69 (m, 2H), 1.641.54 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H), 1.070.90 (m, 6H); 13C NMR (101 MHz, CDCl3) 162.9, 156.5, 135.0, 133.5, 131.0, 126.5, 124.1, 120.2, 113.0, 79.4, 38.2, 32.8, 29.1, 23.5, 22.7, 21.3, 16.4, 14.3, 13.9; IR (KBr) max 3158, 2956, 2863, 1649, 1458, 1351, 1272, 1179, 1071 cm1; HRMS (ESI) for C19H26NO2 (M+H)+: calcd. 300.1964, found 300.1967. 4-Butyl-9-methyl-3-phenyl-8,9-dihydrofuro[2,3-h]isoquinolin-1(2H)-one (4jm).7a Following the general procedure GP-2, compound 4jm (48 mg, 58%) was obtained as colorless crystalline solid; m.p. ACS Paragon Plus Environment

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= 221225 C; Rf  0.80 (7:3 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 9.46 (bs, 1H), 7.62 (d, J  8.8 Hz, 1H), 7.537.43 (m, 5H), 7.26 (d, J  8.8 Hz, 1H), 4.64 (t, J  8.2 Hz, 1H), 4.42 (dd, J  8.4, 1.6 Hz, 1H), 4.244.11 (m, 1H), 2.672.57 (m, 2H), 1.631.51 (m, 2H), 1.35 (d, J  6.8 Hz, 3H), 1.331.26(m, 2H), 0.85 (t, J 7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) 161.7, 158.4, 135.8, 134.3, 132.7, 132.6, 129.1 (2C), 128.7, 128.6 (2C), 124.6, 115.6, 114.6, 79.7, 37.7, 32.8, 27.5, 22.7, 21.3, 13.7; IR (KBr) max 2957, 2930, 2849, 1664, 1482, 1352, 1244 cm1 ; HRMS (ESI) for C22H24NO2 (M+H)+: calcd. 334.1087, found 334.1086. General Procedure for Annulation of furano-isoquinoline (4) with 1,2-Diarylalkynes (GP-3): The annulation reactions were conducted in a 50 mL Schlenk tube having high-pressure valve and side arm. The tube was charged with furano-isoquinolone (4, 0.20 mmol, 1.0 equiv), alkyne (2; 0.40 mmol, 2.0 equiv), [RuCl2(p-cymene)]2 (11.0 mg, 0.0187 mmol, 0.075 equiv), and Na2CO3 (53.0 mg, 0.40 mmol, 2.0 equiv) Cu(OAc)2·H2O (110 mg, 0.55 mmol). Chlorobenzene (PhCl, 2.0 mL) was added to the mixture and the resulting mixture was stirred at 130 oC for 1618 h. The reaction mixture was filtered through a plug of Celite and washed with dichloromethane (3 × 5.0 mL). The solvents were evaporated under the reduced pressure and the crude material was purified using column chromatography on silica gel (10% n-hexane/EtOAc eluent) to give the desired product. 11,12-Bis(4-(tert-butyl)phenyl)-1,1-dimethyl-6-phenyl-1H-furo[2,3-h]isoquinolino[2,1b]isoquinolin-14(2H)-one (6aab). Following the general procedure GP-3, compound 6aab (91 mg, 70%) was obtained as yellow crystalline solid; m.p.  299300 C; Rf  0.58 (9:1 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) 7.607.50 (m, 5H), 7.29 (d, J  8.4 Hz, 2H), 7.246.97 (m, 11H), 6.906.83 (m, 1H), 4.27 (s, 2H), 1.33 (s, 9H), 1.27 (s, 6H), 1.23 (s, 9H);

13

C NMR (101 MHz, CDCl3) 162.2,

159.2, 149.5, 149.1, 139.4, 136.5, 134.5, 133.23, 133.16, 133.1, 133.0, 132.1, 131.1, 130.9, 129.6, 128.7, 128.3, 127.9, 127.7, 127.3, 126.0, 125.8, 125.6, 124.5, 124.1, 123.9, 116.3, 115.5, 86.4, 44.2, 34.4, 34.2, 31.3, 31.1, 26.1; IR (Neat) max 2961, 1753, 1680, 1593, 1479, 1453, 1267 cm1; HRMS (ESI) for C47H46NO2 (M+H)+: calcd. 656.3529, found 656.3527. ACS Paragon Plus Environment

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11-(4-Acetylphenyl)-1,1-dimethyl-6,12-diphenyl-1H-furo[2,3-h]isoquinolino[2,1-b]isoquinolin14(2H)-one

&

12-(4-acetylphenyl)-1,1-dimethyl-6,11-diphenyl-1H-furo[2,3-h]isoquinolino[2,1-

b]isoquinolin-14(2H)-one (6aan). Following the general procedure GP-3, compound 6aan (87 mg, 75%) was obtained as inseparable mixture of both regioisomer as yellow colour solid; m.p.  145147 

C; Rf  0.60 (7:3 hexane/EtOAc); 1H NMR (500 MHz, CDCl3) 7.89 (d, J = 8.0 Hz, 1H), 7.69 (d, J =

8.0 Hz, 2H), 7.597.48 (m, 8H), 7.356.97 (m, 15H), 6.936.85 (m, 2H), 4.26 (s, 3.16H), 2.61 (s, 1.63H), 2.52 (s, 3.10H), 1.25 (s, 3.17H) 1.24 (s, 6H);

13

C NMR (101 MHz, CDCl3) 197.7, 197.6,

161.9, 161.7, 159.6, 159.5, 142.7, 141.8, 139.1, 137.0, 136.5, 135.8, 135.6, 135.0, 133.5, 133.03, 132.98, 132.5, 132.2, 132.0, 131.8, 131.3, 130.53, 130.49, 129.69, 129.67, 129.15, 129.07, 128.5, 128.4, 128.1, 128.0, 127.95, 127.93, 127.89, 127.7, 127.5, 127.4, 127.2, 126.93, 126.89, 126.7, 126.5, 125.8, 125.2, 125.1, 124.1, 123.9, 117.2, 117.0, 115.9, 115.7, 86.44, 86.40, 44.3, 44.2, 26.52, 26.46, 26.2, 26.1; IR (Neat) max 3054, 2946, 2915, 1665, 1593, 1474, 1453, 1319, 1272, 1009 cm1 ; HRMS (ESI) for C41H32NO3 (M+H)+: calcd. 586.2382, found 586.2381. 11,12-Bis(4-chlorophenyl)-1,1-dimethyl-6-phenyl-1H-furo[2,3-h]isoquinolino[2,1-b]isoquinolin14(2H)-one (6aaf). Following the general procedure GP-3, compound 6aaf (80 mg, 66%) was obtained as yellow crystalline solid; m.p.  244246 C; Rf  0.50 (9:1 hexane/EtOAc); 1H NMR (500 MHz, CDCl3) 7.587.44 (m, 5H), 7.307.26 (m, 2H), 7.186.94 (m, 11H), 6.906.83 (m, 1H), 4.26 (s, 2H), 1.27 (s, 6H);

13

C NMR (101 MHz, CDCl3) 161.8, 159.7, 139.1, 135.8, 135.5, 134.6, 133.5, 133.3,

133.0, 132.8, 132.6, 132.3, 132.1, 130.5, 129.7, 128.53, 128.48, 128.1, 128.0, 127.69, 127.67, 126.7, 125.5, 125.4, 124.0, 117.2, 115.9, 86.5, 44.3, 26.1; IR (Neat) max 2951, 2930, 1675, 1593, 1479, 1458, 1350, 1319, 1272, 1086 cm1; HRMS (ESI) for C39H27Cl2NO2 (M)+: calcd. 611.1419, found 611.1419. 1,1-Dimethyl-6-phenyl-11,12-dipropyl-1H-furo[2,3-h]isoquinolino[2,1-b]isoquinolin-14(2H)-one (6aah). Following the general procedure GP-3, compound 6aah (38 mg, 40%) was obtained as yellow crystalline solid; m.p.  166167 C; Rf  0.58 (9:1 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) ACS Paragon Plus Environment

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7.507.42 (m, 4H), 7.407.34 (m, 2H), 7.257.17 (m, 1H), 7.15 (d, J  8.8 Hz, 1H), 7.08 (d, J  8.8 Hz, 1H), 6.88 (dd, J  8.2 & 1.0 Hz, 1H), 6.836.75 (m, 1H), 4.38 (s, 2H), 3.06 (t, J  7.6 Hz, 2H), 2.772.69 (m, 2H), 1.70 (s, 6H), 1.691.61 (m, 2H), 1.461.37 (m, 2H), 1.08 (t, J  7.2 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) 161.6, 159.4, 139.3, 136.4, 133.1, 132.7, 132.3, 130.8, 129.4, 128.5, 127.8, 127.4, 125.3, 123.8, 122.7, 122.2, 117.1, 115.5, 86.4, 44.6, 30.2, 30.0, 26.5, 23.1, 21.5, 14.4, 13.8; IR (Neat) max 3059, 2956, 2874, 1660, 1593, 1453, 1324, 1272, 1190 cm1 ; HRMS (ESI) for C33H34NO2 (M+H)+: calcd. 476.2590, found 476.2590. 1-Ethyl-11,12-bis(4-fluorophenyl)-1-methyl-6-phenyl-1H-furo[2,3-h]isoquinolino[2,1b]isoquinolin-14(2H)-one (6nae). Following the general procedure GP-3, compound 6nae (79 mg, 67%) was obtained as yellow crystalline solid; 1H NMR (400 MHz, CDCl3) 7.567.44 (m, 5H), 7.187.09 (m, 4H), 7.096.94 (m, 7H), 6.906.83 (m, 1H), 6.77 (t, J = 7.0 Hz, 2H), 4.42 (d, J  7.2 Hz, 1H), 4.18 (d, J  6.8 Hz, 1H), 2.001.89 (m, 1H), 1.471.36 (m, 1H), 1.24 (s, 3H), 0.59 (t, J  6.0 Hz, 3H);

13

C NMR (101 MHz, CDCl3) 162.8, 162.3, 161.7, 160.8, 160.3, 139.2, 135.8, 133.42, 133.39,

133.03, 132.97, 132.6, 132.15, 132.09, 131.5, 130.9, 130.8, 130.5, 129.69, 129.66, 128.5, 128.1, 128.0, 127.9, 127.8, 126.5, 125.7, 125.4, 124.4, 117.3, 115.6, 115.2, 115.0, 114.3, 114.2, 83.6, 48.5, 31.0, 25.4, 9.5 (the presence of two ‘F’-moiety on the periphery of 6nae makes the 13C NMR spectrum complex; all the observed peaks are therefore mentioned);

19

F NMR (126 MHz, CDCl3)  114.74, 115.02; IR

(Neat) max 2961, 2915, 1752, 1670, 1598, 1505, 1453, 1226, 1004 cm1; HRMS (ESI) for C40H30F2NO2 (M+H)+: calcd. 594.2245, found 594.2245. General Procedure for the Unsymmetrical Three-fold CH Functionalization (Intramolecular Hydroarylation & Intermolecular annulation) Reaction (GP-4): The three-fold CH functionalization reactions were conducted in a 50 mL Schlenk tube having high pressure valve and side arm. The tube was charged with (1, 0.20 mmol), alkyne (2, 0.60 mmol), [Ru(p-cymene)Cl2]2 (13.0 mg, 10.0 mol %), and Cu(OAc)2·H2O (120 mg, 0.3 mmol). Subsequently, the additive AgSbF6 (27.0 mg, 0.08 mmol) was ACS Paragon Plus Environment

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introduced to the flask in a glove box. 1,2-Dichloroethene (DCE) (1.0 mL) was added to the mixture and the resulting mixture was stirred at room temperature for 2 h then 1,4-dioxane (2 mL) was added to the reaction mixture followed by heating the resulting mixture at 130 oC for 24 h. The reaction mixture was filtered through a plug of Celite and washed with dichloromethane (3 × 5.0 mL). The solvents were evaporated under the reduced pressure and the crude material was purified using column chromatography on silica gel (10% n-hexane/EtOAc eluent) to give the desired product. 1,1-Dimethyl-6,11,12-triphenyl-1H-furo[2,3-h]isoquinolino[2,1-b]isoquinolin-14(2H)-one

(6aaa).

Following the general procedure GP-4, compound 6aaa (55 mg, 51%) was obtained as yellow crystalline solid; m.p. > 350 °C; Rf  0.73 (8:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3)

7.607.48 (m, 5H), 7.337.21 (m, 3H), 7.217.14 (m, 3H), 7.147.01 (m, 8H), 7.00 (d, J = 8.5 Hz, 1H), 6.906.83 (m, 1H), 4.26 (s, 2H), 1.26 (s, 6H); 13C NMR (101 MHz, CDCl3) 162.0, 159.4, 139.3, 137.5, 136.4, 136.3, 133.4, 133.0, 132.9, 132.1, 131.5, 130.8, 129.6, 129.2, 129.1, 128.4, 127.95, 127.88, 127.82, 127.5, 127.2, 126.9, 126.5, 126.25, 126.20, 125.6, 124.1, 116.7, 115.6, 86.5, 44.3, 26.1; IR (Neat) max 2925, 2848, 1768, 1673, 1479, 1457, 1269, 1071 cm1; HRMS (ESI) for C39H30NO2 (M+H)+: calcd. 544.2277, found 544.2277. 9-Chloro-6,11,12-tris(4-chlorophenyl)-1,1-dimethyl-1H-furo[2,3-h]isoquinolino[2,1 b]isoquinolin14(2H)-one (6aff). Following the general procedure GP-4, compound 6aff (61 mg, 45%) was obtained as yellow crystalline solid; m.p. > 350 °C (mass loss observed at 300



C); Rf  0.74 (8:2

hexane/EtOAc); 1H NMR (500 MHz, CDCl3) 7.53 (d, J  10.0 Hz, 2H), 7.39 (m, J  10.5 Hz, 2H), 7.29 (d, J 10.5 Hz, 2H), 7.117.04 (m, 6H), 7.036.94 (m, 3H), 6.89 (bs, 2H), 4.26 (s, 2H), 1.24 (s, 6H);

13

C NMR (125 MHz, CDCl3) 161.6, 159.9, 137.1, 136.7, 135.2, 134.4, 134.3, 134.1, 133.9,

133.63, 133.59, 133.3, 132.8, 132.6, 132.4, 130.3, 130.2, 129.8, 129.7, 128.7, 127.7, 127.3, 126.9, 126.0, 124.9, 124.2, 124.1, 116.2, 116.1, 86.4, 44.3, 26.0; IR (Neat) max 2951, 2915, 2889, 1675, 1593, 1469, 1319, 1272 cm1; HRMS (ESI) for C39H26Cl4NO2 (M+H)+: calcd. 680.0718, found 680.0714. ACS Paragon Plus Environment

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1,1,4-Trimethyl-6,11,12-triphenyl-1H-furo[2,3-h]isoquinolino[2,1-b]isoquinolin-14(2H)-one (6baa). Following the general procedure GP-4, compound 6baa (53 mg, 48%) was obtained yield as yellow crystalline solid; m.p. > 350 °C; Rf  0.75 (8:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3)

7.587.45 (m, 6H), 7.257.19 (m, 2H), 7.197.14 (m, 2H), 7.127.07 (m, 4H), 7.066.99 (m, 3H), 6.996.90 (m, 2H), 6.876.79 (m, 1H), 4.24 (s, 2H), 2.23 (s, 3H), 1.23 (s, 6H);

13

C NMR (101 MHz,

CDCl3) 162.0, 158.3, 139.4, 137.6, 136.4, 136.3, 133.1, 132.9, 132.5, 132.2, 131.5, 130.9, 129.6, 129.0, 128.4, 128.0, 127.91, 127.88, 127.7, 127.6, 127.2, 126.8, 126.6, 126.5, 126.2, 126.0, 125.5, 122.3, 116.6, 86.3, 44.5, 26.2, 16.2; IR (Neat) max 3054, 3018, 2956, 1732, 1670, 1598, 1474, 1438, 1288 cm1; HRMS (ESI) for C40H32NO2 (M+H)+: calcd. 558.2433, found 558.2433. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org Detailed experimental procedures and the physical properties of the compounds [NMR data, characterization, spectra, and X-ray crystallographic data (CIF)]. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; [email protected]; [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT


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We thank SERB (EMR/2014/385) for financial support and University of Hyderabad (UoH; UPECAS and PURSE-FIST) for overall facility. K. G., M.S., G.D. thanks CSIR, India for fellowship. REFERENCES 1. CH activation in synthesis; see: (a) Godula, K.; Sames, D. CH Bond Functionalization in Complex Organic Synthesis. Science 2006, 312, 67. (b) Davies, H. M. L.; Bois, J. D.; Yu, J.-Q. C– H Functionalization in organic synthesis. Chem. Soc. Rev. 2011, 40, 1855 and reference therein. (c) Chen, D. Y.-K.; Youn, S. W. C-H Activation: A Complementary Tool in the Total Synthesis of Complex Natural Products. Chem.-Eur. J. 2012, 18, 9452. 2. (a) Nairoukh, Z.; Cormier, M.; Marek, I. Merging C–H and C–C bond cleavage in organic synthesis. Nature Rev. Chem. 2017, 1, 0035. (b) Jean, M.; van de Weghe, P. Transition Metal CH Activation: Application to Stereoselective Synthesis of Natural Products and Drugs; Andrushko, V.; Andrushko, N., Eds.; John Wiley & Sons, Inc., 2013; 667 (c) Davies, H. M. L.; Morton, D. Recent Advances in C–H Functionalization. J. Org. Chem., 2016, 81, 343. (d) Ito, H.; Ozaki, K.; Itami, K. Annulative π-Extension (APEX): Rapid Access to Fused Arenes, Heteroarenes, and Nanographenes. Angew. Chem., Int. Ed., 2017, 56, 11144. 3. (a) Zheng, L.; Hua, R. C–H Activation and Alkyne Annulation via Automatic or Intrinsic Directing Groups: Towards High Step Economy Chem. Rec. doi: 10.1002/tcr.201700024. (b) Bering, L.; Manna, S.; and Antonchick.; A. P. Sustainable, Oxidative, and Metal-Free Annulation Chem. -Eur. J. 2017, 23, 10936. 4. (a) Ichikawa, M.; Takahashi, M.; Aoyagi, S.; Kibayashi, C. Total Synthesis of (−)-Incarvilline, (+)Incarvine C, and (−)-Incarvillateine. J. Am. Chem. Soc. 2004, 126, 16553. (b) Delord, J. W.; Glorius, F. CH bond activation enables the rapid construction and late-stage diversification of functional molecules. Nature Chemistry 2013, 5, 369. 5. Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Constructing Multiply Substituted Arenes Using Sequential Pd(II)-Catalyzed C–H Olefination. Angew.Chem., Int. Ed. 2010, 49, 6169. 6. Examples of unsymmetrical bis-functionalization with different functionalities; see: (a) Vickers, C.; Mei, T.-S.; Yu, J.-Q. Pd(II)-Catalyzed o-C−H Acetoxylation of Phenylalanine and Ephedrine Derivatives with MeCOOOtBu/Ac2O. Org. Lett. 2010, 12, 2511. (b) Wang, H.; Li, G.; Engle, K. M.; Yu, J.-Q.; Davies, H. M. L. Sequential C–H Functionalization Reactions for the Enantioselective Synthesis of Highly Functionalized 2,3-Dihydrobenzofurans. J. Am. Chem. Soc. 2013, 135, 6774. (c) Rosen, B. R.; Simke, L. R.; Thuy-Boun, P. S.; Dixon, D. D.; Yu, J.-Q.; Baran, P. S. CH Functionalization Logic Enables Synthesis of (+)-Hongoquercin A and Related Compounds. Angew. Chem., Int. Ed. 2013, 52, 7317. (d) Sarkar, D.; Gulevich, A. V.; Melkonyan, F. S.; Gevorgyan, V. Synthesis of Multisubstituted Arenes via PyrDipSi-Directed Unsymmetrical Iterative C–H Functionalizations. ACS. Catal. 2015, 5, 6792. 7. (a) Ghosh, K.; Rit, R. K.; Ramesh, E.; Sahoo, A. K. Ruthenium-Catalyzed Hydroarylation and One-Pot Twofold Unsymmetrical C−H Functionalization of Arenes Angew. Chem. Int. Ed. 2016, 55, 7821. (b) Wu, Y.; Chen, Z.; Yang, Y.; Zhu, W.; Zhou. Rh(III)-Catalyzed Redox-Neutral Unsymmetrical C–H Alkylation and Amidation Reactions of N-Phenoxyacetamides B. J. Am. Chem. Soc. 2018, 140, 42. (c) Li, W.; Zhao, Y.; Mai, S.; Song, Q. Thiocarbamate-Directed ACS Paragon Plus Environment

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