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Construction of Pyranoisoquinolines via Ru(II)-Catalyzed Unsymmetrical Double Annulation of N-Methoxybenzamides with Unactivated Alkynes Tirumaleswararao Guntreddi, Majji Shankar, Nagarjuna Kommu, and Akhila Kumar Sahoo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01878 • Publication Date (Web): 14 Aug 2019 Downloaded from pubs.acs.org on August 14, 2019

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The Journal of Organic Chemistry

Construction of Pyranoisoquinolines via Ru(II)Catalyzed Unsymmetrical Double Annulation of N-Methoxybenzamides with Unactivated Alkynes Tirumaleswararao Guntreddi,†a Majji Shankar,†a Nagarjuna Kommu,b and Akhila K. Sahoo*ab a

b

School of Chemistry, University of Hyderabad, Hyderabad-500046, India

Advanced Center of Research in High Energy Materials (ACRHEM), University of Hyderabad, Hyderabad-500046, India

[email protected], [email protected]

RECEIVED DATE (to be automatically inserted)

A ruthenium (Ru)-catalyzed double annulation of easily accessible N-methoxybenzamide derivatives with unactivated alkynes for the synthesis of unusual 6,6-fused pyranoisoquinolines is described. Both ortho-CH bonds of arenes as well the N- and O-moieties of Nmethoxybenzamides are involved for the construction of four [(C–C)(C–N) and (CC)(CO)] bonds in one step under single catalytic conditions. The unsymmetrical annulation of Nmethoxybenzamides with two distinct alkynes is also demonstrated. The oxidizable directing group N-methoxyamine (NHOMe) assists the unsymmetrical double annulations of arenes [that

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uses both N- and O-heteroatoms] in a single operation. This synthetic method features excellent substrate scope and tolerates wide range of functional groups. Peripheral modification of pyranoisoquinolines for the construction of complex heterocyclic compounds is also demonstrated. Introduction Nitrogen and oxygen-containing polycyclic heterocycles are unequivocally important, as these structures are largly found in biologically active molecules, natural products, pharmaceuticals, advanced materials, and ligands (Figure 1).1,2 In this context, the synthetically viable transitionmetalcatalyzed directing group (DG) promoted annulation of inert CH bonds has principally been found beneficial for the fabrication of complex heterocycles.3,4 Thus, the domain of monoannulation strategies have widely been investigated by roping heteroatom of the DG along with inert CH bonds (close proximity to the DG) of the molecular scaffold, and/or a connecting unit (olefin/alkyne/carbene etc).3,57 In addition, multiple CH bonds have been used in the development of stepwise (under different catalytic conditions; Scheme 1A) and sequential (one catalytic system with successive addition of reactive agents; Scheme 1A) annulation methods for the construction of -extended fused heterocycles.8,9 However, in most cases a single o-CH bond of the parent hetero(arene) motif has exclusively been involved in the double annulations with alkynes accessing linearly fused -extended heterocycles (path I, Scheme 1B).9,10 On the other hand, both o-CH bonds of hetero(arenes) for the identical double annulation with alkynes to the synthesis of angularly fused -extended heterocycle has been less explored (path II, Scheme 1B);11 mainly the molecular rigidity and conformation strain obstruct this challenging transformation.8,12 Moreover, the undisputed concerns, i.e. uncontrolled reactivity and the lack of selectivity attenuated in each annulation, and the catalyst dependable DG-assisted


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functionalization of a particular o-CH bond, enforce making the angular double annulations ineffective (path II, Scheme 1B).11 Inspite of these challenges, both o-CH bonds of benzoylacetonitrile,11a enaminoester,11c or polyaromatic aldehyde11d have successfully been employed for the one-pot double annulation with alkynes in the presence of rhodium (Rh)catalyst. All these synthetic manifestations led to 6,6-bifused heteroaryls, simultaneously constructing CC along with CO/CN bonds in a single operation. The benzonaphthyridine scaffold has been fabricated from the Rh-catalyzed symmetrical double annulation of Nhydroxybenzamidines with alkynes forming two CC/CN bonds in a single operation.11b The symmetrical oxidative double annulation of aryl imidazolium salts with alkynes has also been viable under Rh-catalysis making benzo[ij]imidazo[2,1.5-de]quinolizinium salts with four CC bonds.13 A recent studies of Ru-catalyzed transformable methylphenyl sulfoximine (MPS) aided twofold unsymmetrical double annulation of hetero(arenes) with alkynes has led to 6,6-fused pyranoisoquinoline.14 Nevertheless, the use of non-commercial DG is essential for this conversion. Thus, surveying an identical transformation for the one-pot functionalization of multiple CH bonds under the assistance of a commericailly available DG is always desirable.

Figure 1. Nitrogen and Oxygen bearing Heterocyclic Compounds Inspired from the broad synthetic potential of readily accessible N-OMe oxidizable group enabled benzamides in the domain of CH activation strategies,5a,6 we turned our attention



probing the unsymmetrical double annulation of N-methoxybenzamides (involving both N- and O-moieties) with alkynes, which to the best of our knowledge remains elusive. Moreover, the Nmethoxybenzamide derivatives have extensively been used for the development of novel annulation methods under the influence of various transition metal catalysts [i.e. Pd, Rh, Ru, Co, Ir, etc.]; however, most of the transformations are confined to mono-annulation accessing isoquinolone scaffolds.5a,6 Based on our current research interest to the one-pot functionalization of multiple inert CH bonds,9,14 we became interested stitching the OHtautomer of isoquinolone (obtained in situ from the mono-annulation between N-methoxybenzamide and alkyne) with alkyne to construct 6,6-fused pyranoisoquinoline (Scheme 1C).7 We herein discussed a one-pot unsymmetrical double annulation of N-methoxybenzamides both o-CH bonds with two molecules of identical/dissimilar alkynes under single catalytic systems; the transformation works well in the presence of air-stable, less-expensive Ru-catalyst and builds a wide range of unusual pyranoisoquinolines (Scheme 1C).


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Scheme 1. Unsymmetrical Multiple Annulations of Arenes

RESULTS AND DISCUSSION To probe the synthesis of pyranoisoquinoline, the study was commenced performing a double annulation of N-methoxybenzamide with alkyne under Ru-catalysis. To start with, a model reaction between N-methoxy-p-methyl benzamide (1a) and 4-octyne (2a) was surveyed under Ru-catalysis (Table 1). To our delight, the expected pyranoisoquinoline 3a was formed in 68% yield, under the catalytic conditions [RuCl2(p-cymene)]2 (10 mol %) and AgSbF6 (40 mol %) in



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dioxane at 120 °C for 24 h (entry 1). Moreover, solvents like CH3CN and toluene were not suitable (entries 2 and 3). Gratifyingly, 3a was isolated in 82% yield when the reaction conducted in ClCH2CH2Cl (1,2-DCE) (entry 4). The other additives, such as: KPF6, NaPF6, and Table 1. Optimization of Reaction Conditionsa

Ru-cat entry

(mol %)

additive (40 mol %)

acetate source

yield solvent

3a (%)b

(1.5 equiv)

1

10

AgSbF6

Cu(OAc)2·H2O

1,4-dioxane

68

2

10

AgSbF6

Cu(OAc)2·H2O

CH3CN

trace

3

10

AgSbF6

Cu(OAc)2·H2O

toluene

17

4

10

AgSbF6

Cu(OAc)2·H2O

1,2-DCE

82

5

10

KPF6

Cu(OAc)2·H2O

1,2-DCE

trace

6

10

NaPF6

Cu(OAc)2·H2O

1,2-DCE

trace

7

10

AgBF4

Cu(OAc)2·H2O

1,2-DCE

28

8

6

AgSbF6

Cu(OAc)2·H2O

1,2-DCE

56

9

8

AgSbF6

Cu(OAc)2·H2O

1,2-DCE

65

10

9

AgSbF6

Cu(OAc)2·H2O

1,2-DCE

74

11

10

AgSbF6

Mn(OAc)2

1,2-DCE

21

12

10

AgSbF6

KOAc

1,2-DCE

16

13

10

AgSbF6

NaOAc

1,2-DCE

15


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a

Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), [RuCl2(p-cymene)]2 (10 mol %), AgSbF6 (40 mol

%), Cu(OAc)2·H2O (0.45 mmol), solvent (2.0 mL) at 120 °C for 24 h. bIsolated yield. NR = No reaction

AgBF4 were found inferior in comparison to AgSbF6 (entries 57). The reaction in presence of less amount catalyst loading, i.e. 6.0 mol %, 8.0 mol %, and 9.0 mol % independently led to the product in 56%, 65%, and 74% yield, respectively (entries 810). Screening of Mn(OAc)2, KOAc, or NaOAc provided inferior result (entries 1113). The effect of various amide-DG for this one-pot double annulation of o-CH bonds of arene was next probed under the optimized conditions (Table 1). The NHMe (I) bearing amide failed to deliver the double annulation product 3a. On the other hand, moderate amount of 3a was formed when the reaction of simple amide (II) or the amides with internal oxidizable moiety [i.e NN/NO bonded amides; III, IV, and V] were independently carried out with 2a. Whereas the double annulation of the protected oxidizable amide VI with 2a was found moderate yielding 49% 3a.57 Thus, NHOMe−DG was proved vital in this interesting one-pot unsymmetrical double annulations of arenes with 2a to construct 6,6-fused pyranoisoquinoline 3a (entry 4, Table 1). Under the optimized reaction conditions shown in entry 4, Table 1, the scope of various structurally diverse N-methoxyamide derivatives 1 for the double annulation with 4-octyne was at first examined. The electron-rich Nmethoxyamide derivatives having substituents, methyl (Me), t-butyl (tBu), methoxy (OMe), and phenoxy (OPh) at the para position of the arene ring were reacted efficiently with 2a to yield the respective products 3a (82%), 3b (77%), 3c (63%), and 3d (66%). Likewise, the coupling of electron-neutral N-methoxybenzamide with 2a afforded 78% 3e. The labile halo groups, fluoro, chloro, and bromo were well tolerated under the catalytic conditions, providing the peripheral substituted pyranoisoquinolines 3f–h in moderate yields. The desired 6,6-fused pyranoisoquinolines 3il were constructed from the annulation of p-phenyl



and p-electron-withdrawing group substituted arene enabled N-methoxybenzamide derivatives with 2a or 3-hexyne (2b). Scheme 2. Double Annulation of Amides with Alkynesa

a

Reaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), [RuCl2(p-cymene)]2 (10 mol %), AgSbF6 (40 mol %),

Cu(OAc)2·H2O (0.45 mmol), 1,2-DCE (2.0 mL) at 120 °C for 24 h. NR = No reaction


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The transformable nitro and ester group did not affect the reactivity as well the productivity. Likewise, the m-Me substituted N-methoxybenzamide is provided moderate yield of 3m along with trace of other isomer. The other symmetrical dialkyl alkynes, 3-hexyne (2b), 5-decyne (2c), and 1,4-dimethoxy-2-butyne (2d) were successfully coupled with 1a to build the respective pyranoisoquinolines 3np in appreciable yields. Disappointingly, 1,4-dichloro-2-butyne (2e) did not deliver the desired product with 1a; presumably the alkyne and the product are not so stable under the harsh condition in the presence of acetate source. Unsurprisingly, the annulation of ortho-substituted N-methoxybenzamide with 2b exclusively yielded the mono-annulated isoquinolone product 3r (87%); the non-availability of o′-CH bond of arene consequently obstructs the oxidative second annulation. 15 Scheme 3. Unsymmatrical Annulations of N-Methoxybenzamide

Motivated by the successful double annulation of arenes with aliphatic alkynes (Scheme 2), we next performed the identical transformation exploring two distinct alkynes. We anticipate that each alkyne would be able to undergo annulations with the respective N-methoxybenzamide derivative to provide mixture of products [symmetrical double annulation with 1,2-dialkyl alkyne to provide A, double annulation with 1,2-diaryl alkyne to linearly fused -extended heterocycle B, unsymmetrical double annulation at first with 1,2-diaryl alkyne and then with 1,2-dialkyl



alkyne to linearly fused -extended heterocycle C, and finally, the desired product D formed through unsymmetrical double annulation at first with 1,2-dialkyl alkyne and then with 1,2-diaryl alkyne; Scheme 3), as each step of the annulation does not necessarily run to completion. 9b,10,14 To avoid the competitive annulations associated from each alkyne and the formation of several byproducts from incomplete/nonselective annulation, a two-step synthetic strategy has therefore been planned. Thus, the first step involves a NHOMe-promoted o-C−H monoannulation with 1,2-dialkyl alkyne, and the second step comprises the C(8)−H activation and the annulation of isoquinolone, obtained from the first step, with structurally diverse alkynes. In this regard, the formation of respective isoquinolone 4 from the cyclization between 1 and 2 under Ru-catalyst in presence of proton source is at first envisaged; we believe the proton source would help the protodemetalation and would deliver the mono-annulation product.5a Next, second annulation of 4 with other unactivated alkyne under the Ru-catalyzed oxidative conditions would yield the desired unsymmetrically fused pyranoisoquinoline 5. Importantly, both the annulations can be performed under Ru-catalysis. As expected, the isoquinolone motif 4a (89%) was fabricated from the monoannulation of 1a with 2a when the reaction was performed under Ru catalysis in the presence of NaOAc in MeOH (Conditions A, Scheme 4). Next, the annulation of isoquinolone 4a with 1,2-diaryl/alkyl alkynes in presence of the catalytic conditions [[RuCl2(p-cymene)]2 (5.0 mol %), AgSbF6 (20 mol %), Cu(OAc)2·H2O (1.0 equiv) in DCE at 120 °C for 15 h] provided the respective peripheral decorated 6,6-fused pyranoisoquinolines (Conditions B, Scheme 4). The independent annulation of 4a with electron-neutral 1,2-diphenyl acetylene (2f), electron-rich 1,2-diaryl alkynes having substitutions [p-tBu (2g), p-OMe (2h), m-Me (2l)] on arene, and/or the electron-poor 1,2-diaryl alkynes with substitutions [p-F (2i), p-Cl (2j), p-COMe (2k)] on arene successfully yielded the


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Scheme 4. Sequential Double Annulation of N-Methoxybenzamides with Different Alkynesa

a

Reaction conditions-A: 1 (0.5 mmol), 2 (0.6 mmol), [RuCl2(p-cymene)]2 (3.0 mol %), NaOAc (20 mol

%), MeOH (3.0 mL) at rt for 10 h. Reaction conditions-B: 4 (0.3 mmol), 2 (0.36 mmol), [RuCl2(pcymene)]2 (5.0 mol %), AgSbF6 (20 mol %), Cu(OAc)2·H2O (0.30 mmol), 1,2-DCE (2.0 mL) at 120 °C for 15 h.



respective unsymmetrical 6,6-fused pyranoisoquinolines 5a (75%), 5b (89%), 5c (77%), 5d (90%), 5e (48%), 5f (75%), and 5g (75%). Likewise, unsymmetrical double annulation product 5h was accessed from the reaction between 4a and 3-hexyne (2b) in 59% yield. Moreover, the annulation of an unsymmetrical 1-phenyl-1-hexyne (2m) and 4a occurred with high regioselectivity yielding 5i in 76% yield; a consequence with the incorporation of an aryl moiety close proximity to the O-heteroatom. However, the reaction between 4a and unsymmetrical 1,2diaryl alkyne 2n provided inseparable mixture of 5j/5j′ (3:2). Similarly, the isoquinolone scaffolds 4b (86%) and 4c (87%) were synthesized from the mono-annulation of 1i and/or 1h with 3-hexyne (2b), respectively under the catalytic conditions A (Scheme 4). Finally, independent annulation of 4b/4c with 2m led to 5k and 5l in 78% and 72% yield, respectively (Scheme 4). Finally, we performed the two-fold unsymmetrical annulations of 1a with two distinct alkynes (Scheme 5). Several trials of attempts finally delivered the desired pyrano-isoquinoline 6 under the following synthetic operations in one pot [reaction of 1a with 2b was conducted at 60 °C for 4 h at first; next, other alkyne 2g/2f was added and the resulting mixture heated at 120 °C for 20 h]. Thus, different alkynes were successively participated in sequential double annulations under one catalytic condition to afford 6a and 6b in 57% and 71% yield, respectively (Scheme 5).16 Scheme 5. One-Pot Double Annulation of 1a with Different Alkynesa


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a

Reaction conditions: 1a (0.3 mmol), 2b (0.3 mmol), [RuCl2(p-cymene)]2 (10 mol %), AgSbF6 (40 mol

%), Cu(OAc)2·H2O (0.45 mmol) in 1,2-DCE (2.0 mL) at 60 °C for 4 h; then other alkyne 2g/2f (0.36 mmol) was added and heated at 120 °C for 20 h.

The gram scale synthesis of 3a (73%, 1.55 g) makes the current transformation scalable and synthetically practical. To further enlarge the molecular scaffold of pyranoisoquinoline, the bromo group on the periphery of 3h has successfully been subjected to the Pd-catalyzed SuzukiMiyaura coupling with benzene-1,4-diboronic acid to construct 7 in 76% yield (Scheme 6).17a Likewise, Sonogashira coupling of 3h with phenylacetylene afforded 8 (84%).17b Interestingly, the Ru-catalyzed o-CH diarylation of 2-phenylpyridine with 3h built a complex molecular architecture 9 (82%) as depicted in Scheme 6.17c Scheme 6. Gram Scale Synthesis and Applicationsa

a

Reaction conditions: (a) 3h (0.20 mmol), benzene-1,4-diboronic acid (0.10 mmol), Pd(PPh3)4 (10 mol

%), K2CO3 (0.25 mmol), THF (1.5 mL), MeOH (1.0 mL), H2O (0.5 mL), at 85 oC for 20 h. (b) 3h (0.20 mmol), phenylacetylene (0.24 mmol), Pd(PPh3)2Cl2 (4.0 mol %), CuI (6.0 mol %), Et3N (0.6 mmol), DMF



(1.5 mL) at 100 oC for 18 h. (c) 2-phenylpyridine (0.1 mmol), 3h (0.25 mmol), [RuCl2(p-cymene)]2 (2.5 mol %), KOAc (0.3 mmol), N-Methyl-2-pyrrolidone (NMP) (1.0 mL) at 120 oC for 5 h.

To gain more insight into the mechanism of this reaction, various control experiments were performed. The deuterium scrambling study of 1e in the presence of 3-hexyne (2b) provided 10 with 38% D incorporation in C8-position (eq 1, Scheme 7). This result indicated the O-directed metalation of the isoquinolone C(8)−H bond. To further probe the C−H activation process, intermolecular KIE experiments were conducted. The kH/kD value for the overall one-step double annulation of 1e-H5 and/or 1e-D5 with 2b is ∼1.13 (competitive) and ∼1.15 (parallel), clearly indicates that C−H cleavage is not involved in the rate-limiting step (eq 2, Scheme 7).16,17 Based on the competition experiments, the electron-rich arenes underwent reaction faster than that of electron-poor arenes. For example, the product ratio 12/13 (3:1) were obtained from the reaction of 1b/1j (p-tBu vs p-NO2) with 2b (eq 3, Scheme 7). Scheme 7. Control and Deuterium Experiments


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On the basis of the previous observations and control experiments, the possible mechanisam for one-pot double annulation of N-methoxybenzamide with unactivated alkynes is shown in Scheme 8.3-5 The coordination of N-moiety of N-methoxybenzamide to the active Ru-catalyst and the activation of proximal o-CH arene bond at first forms the intermediate A. Next, the coordination of alkyne to the cyclometalation complex A and subsequent alkyne insertion provides seven membered Ru-cycle C. The slippage of Ru-species to the oxidizable N-OMe bond of C then results the intermediate D. The protodemetalation of D in presence of protic solvent delivers the mono-annulation isoquinolone product 4. While in the absence of proton source, the imide assisted activation of C(8)-H bond affords a five membered Ru-metalacycle E. The concomitant coordination of alkyne to Ru-species E followed by insertion generates a seven membered oxa-Ru-metalacycle G. Finally, Cu(OAc)2 mediated reductive elimination of G constructs the desired pyranoisoquinoline product 3 and regenerates the active Ru(II)-catalyst for the next cycle (Scheme 8).14 Scheme 8. Plausible Reaction Mechanism



Conclusion In summary, a Ru(II)-catalyzed C–H/N–H and CH/OH oxidative double annulation of Nmethoxybenzamide derivatives with unactivated alkynes for the synthesis of 6,6-fused pyranoisoquinolines has been developed. This transformation primarily functionalizes both oCH bonds of N-methoxybenzamides by uniting N- and O- heteroatoms of the precursor with two molecules of unactivated alkynes. Moreover, the double annulations are successful under a single catalytic system in one-pot. Two distinct alkynes are successfully coupled with Nmethoxybenzamides building diverse ranges of pyranoisoquinolines. The reaction tolerates wide range of common functional groups and exhibits broad scope. The Pd/Ru-catalyzed crosscouplings of labile bromo group on the periphery of pyranoisoquinolines build complex molecular skeletons. The gram scale synthesis of pyranoisoquinoline makes the strategy synthetically workable. 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 or neutral alumina. Thin layer chromatography (TLC) was performed on silica gel GF254 plates and alumina plates. Proton, carbon, and fluorine nuclear magnetic resonance spectra ( 1H NMR, 13C{1H} NMR and 19

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

13

C NMR, 101 MHz; 19F NMR, 376 MHz) and (1H NMR, 500 MHz; 13C{1H} NMR, 126 MHz;

19

F NMR, 470 MHz) having the solvent resonance as internal standard ( 1H NMR, CDCl3 at 7.26

ppm; 13C{1H} NMR, CDCl3 at 77.0 ppm). Few cases tetramethylsilane (TMS) at 0.00 ppm was


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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{1H}

NMR,

19

F NMR were reported in terms of chemical shift (ppm). IR spectra were

reported in cm1. High resolution mass spectra were obtained in ESI mode in Maxis-TOF analyzer. Melting points were determined by electro-thermal heating and are uncorrected. Preparation of N-Methoxybenzamides (1) and Alkynes (2): The benzamides (1an and 1eD5),5a,6c III,6e IV,5g V,6e and VI10c were prepared according to literature procedure. Symmetrical and unsymmetrical alkynes 2g, 2h, 2i, 2j, 2k, 2l and 2n were synthesized following the reported procedures.20 Analytical and spectral data of these compounds are exactly matching with the reported data. The substrates 2a, 2b, 2c, 2d, 2e, 2f, 2m, I, and II were purchased and directly used. General Procedure for the Synthesis of 6,6-Fused Pyrano-Isoquinoline via the Direct Double-Annulation of N-methoxybenzamide derivatives with 1,2-Dialkyl Alkynes (GP-1): The annulation reactions were carried out in a 25 mL screw capped tube. The tube was charged with N-methoxybenzamide derivative (1, 0.3 mmol), alkyne (2, 0.9 mmol), [RuCl2(p-cymene)]2 (18.3 mg, 10 mol %, 0.03 mmol), and Cu(OAc)2·H2O (90 mg, 0.45 mmol). Subsequently, AgSbF6 (41 mg, 40 mol %, 0.12 mmol) was introduced in to the tube in a glove box. The solvent 1,2-dichloroethane (DCE) (2.0 mL) was added to the mixture and the resulting mixture was stirred at 120 C in heating block for 24 h. The reaction mixture was cooled to ambient temperature, filtered through a small plug of Celite and then washed with dichloromethane (3 × 10 mL). The solvents were evaporated under reduced pressure and the crude material was



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purified using column chromatography on neutral aluminia (510% n-hexane/EtOAc eluent) to give the desired product. Following this procedure (GP-1), compounds 3ar were prepared. Analytical and spectral data of these compounds are exactly matching with the reported values. 14 5-Methyl-2,3,7,8-tetrapropylpyrano[4,3,2-ij]isoquinoline (3a): 14 3a (86 mg, 82%); light yellow crystalline solid. mp  113114C; 1H NMR (400 MHz, CDCl3)  7.17 (s, 1H), 6.76 (s, 1H), 2.76 (q, J 7.3 Hz, 4H), 2.542.41 (m, 7H), 1.801.69 (m, 4H), 1.641.53 (m, 4H), 1.080.95 (m, 12H);

13

C{1H} NMR (101 MHz, CDCl3)  157.1, 153.5,

152.0, 141.9, 138.7, 133.4, 121.3, 117.5, 115.2, 113.8, 112.0, 37.1, 32.7, 29.6, 28.4, 23.5, 23.0, 22.9, 21.5, 21.2, 14.4, 14.3, 14.2, 13.8. 5-tert-Butyl-2,3,7,8-tetrapropylpyrano[4,3,2-ij]isoquinoline (3b): 14 3b (91 mg, 77%); pale yellow crystalline solid. mp  124126 C; 1H NMR (400 MHz, CDCl3)

 7.39 (d, J  1.2 Hz, 1H), 7.03 (d, J  1.2 Hz, 1H), 2.862.73 (m, 4H), 2.51 (q, J  8.1 Hz, 4H), 1.811.70 (m, 4H), 1.671.55 (m, 4H), 1.39 (s, 9H), 1.100.96 (m, 12H);

13

C{1H} NMR (101

MHz, CDCl3)  157.0, 154.6, 153.3, 151.9, 138.4, 132.9, 121.8, 113.74, 113.69, 112.2, 112.0, 37.1, 35.4, 32.7, 31.1, 29.5, 28.3, 23.5, 22.9, 21.4, 21.2, 14.4, 14.2,14.1, 13.8. 5-Methoxy-2,3,7,8-tetrapropylpyrano[4,3,2-ij]isoquinoline (3c): 14 3c (70 mg, 63%); pale yellow crystalline solid. mp  129130 C; 1H NMR (400 MHz, CDCl3)  6.71 (d, J  2.0 Hz, 1H), 6.55 (d, J  2. 0 Hz, 1H), 3.91 (s, 3H), 2.792.70 (m, 4H), 2.51 (t, J  7.8 Hz, 2H), 2.42 (t, J  7.8 Hz, 2H), 1.801.69 (m, 4H), 1.651.51 (m, 4H), 1.090.95 (m, 12H);

13

C{1H} NMR (101 MHz, CDCl3)  162.5, 156.8, 154.1, 152.8, 140.5, 135.5, 121.3,


Page 19 of 45 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


111.9, 111.0, 104.5, 97.9, 55.1, 37.3, 32.8, 29.8, 28.5, 23.5, 22.5, 21.4, 21.2, 14.5, 14.3, 14.2, 13.8. 5-Phenoxy-2,3,7,8-tetrapropylpyrano[4,3,2-ij]isoquinoline (3d): 14 3d (86 mg, 66%); pale yellow crystalline solid. mp  163164C; 1H NMR (400 MHz, CDCl3)  7.37 (bt, J  7.4 Hz, 2H), 7.16 (t, J  7.4 Hz, 1H), 7.08 (d, J  8.4 Hz, 2H), 6.81 (s, 1H), 6.65 (s, 1H), 2.73 (t, J  7.8 Hz, 2H), 2.62 (t, J  7.8 Hz, 2H), 2.52 (t, J  7.6 Hz, 2H), 2.38 (t, J  7.8 Hz, 2H), 1.811.70 (m, 4H), 1.551.46 (m, 4H), 1.040.89 (m, 12H); 13C{1H} NMR (101 MHz, CDCl3)  160.6, 156.8, 156.1, 154.3, 152.8, 140.3, 136.1, 129.7, 123.9, 121.5, 119.4, 112.4, 112.0, 106.1, 104.8, 37.1, 32.7, 29.6, 28.4, 23.5, 22.6, 21.3, 21.2, 14.23, 14.20, 14.0, 13.8 2,3,7,8-Tetrapropylpyrano[4,3,2-ij]isoquinoline (3e): 14 3e (79 mg, 78%); light yellow crystalline solid. mp  102103 C; 1H NMR (400 MHz, CDCl3)

 7.53 (t, J 8.0 Hz, 1H), 7.39 (d, J 8.4 Hz, 1H), 6.94 (d, J 7.2 Hz, 1H), 2.822.72 (m, 4H), 2.55-2.40 (m, 4H), 1.801.69 (m, 4H), 1.641.52 (m, 4H), 1.080.96 (m, 12H); 13C{1H} NMR (101 MHz, CDCl3)  157.2, 153.4, 151.9, 138.4, 133.5, 131.7, 121.8, 117.9, 115.5, 113.4, 112.2, 37.1, 32.7, 29.6, 28.4, 23.5, 22.9, 21.4, 21.2, 14.4, 14.3, 14.2, 13.8. 5-Fluoro-2,3,7,8-tetrapropylpyrano[4,3,2-ij]isoquinoline (3f): 14 3f (41 mg, 39%); pale yellow solid. mp  151153 C; 1H NMR (400 MHz, CDCl3)  6.97 (dd, J 11.6 Hz, 2.0 Hz, 1H), 6.65 (dd, J  10.0 Hz, 2.0 Hz, 1H), 2.792.68 (m, 4H), 2.52 (t, J  7.8 Hz, 2H), 2.42 (t, J  8.0 Hz, 2H), 1.831.69 (m, 4H), 1.641.50 (m, 4H), 1.080.96 (m, 12H); 13

C{1H} NMR (101 MHz, CDCl3)  165.5 (d, J  249 Hz), 156.8, 154.9, 153.4, 140.6 (d, J  11

Hz), 137.1 (d, J  11 Hz), 122.0 (d, J  5.0 Hz), 112.7, 112.1, 102.9 (d, J  27 Hz), 102.3 (d, J 



24 Hz), 37.2, 32.8, 29.8, 28.5, 23.5, 22.7, 21.3, 21.2, 14.3, 14.2, 14.1, 13.8; 19F NMR (376 MHz, CDCl3) 105.20. 5-Chloro-2,3-diisopropyl-7,8-dipropylpyrano[4,3,2-ij]isoquinoline (3g): 14 3g (82 mg, 74%); pale yellow. mp  116117 C; 1H NMR (400 MHz, CDCl3)  7.31 (d, J 1.2 Hz, 1H), 6.83 (d, J  1.6 Hz, 1H), 2.772.66 (m, 4H), 2.50 (t, J  7.8 Hz, 2H), 2.39 (t, J  8.0 Hz, 2H), 1.781.66 (m, 4H), 1.601.49 (m, 4H), 1.070.95 (m, 12H); 13C{1H} NMR (101 MHz, CDCl3)  156.8, 154.9, 153.4, 139.4, 138.5, 135.6, 121.4, 117.0, 114.0, 113.7, 111.7, 37.1, 32.7, 29.5, 28.3, 23.4, 22.8, 21.24, 21.19, 14.3, 14.2, 14.1, 13.8. 5-Bromo-2,3,7,8-tetrapropylpyrano[4,3,2-ij]isoquinoline (3h): 14 3h (63 mg, 50%); yellow crystalline solid; mp  146147 C; 1H NMR (400 MHz, CDCl3)  7.51 (s, 1H), 7.00 (s, 1H), 2.792.69 (m, 4H), 2.562.48 (m, 2H), 2.462.37 (m, 2H), 1.801.69 (m, 4H), 1.621.53 (m, 4H), 1.090.96 (m, 12H);

13

C{1H} NMR (101 MHz, CDCl3)  157.0,

154.9, 153.5, 139.7, 135.6, 127.5, 121.3, 120.3, 116.7, 113.9, 111.6, 37.2, 32.8, 29.5, 28.3, 23.4, 22.9, 21.3, 21.2, 14.3, 14.2, 14.1, 13.8. 5-Phenyl-2,3,7,8-tetrapropylpyrano[4,3,2-ij]isoquinoline (3i): 14 3i (73 mg, 58%); pale yellow semi solid; 1H NMR (400 MHz, CDCl3)  7.697.63 (m, 2H), 7.56 (s, 1H), 7.557.48 (m, 2H), 7.477.39 (m, 1H), 7.15 (bs, 1H), 2.902.76 (m, 4H), 2.602.50 (m, H), 1.841.73 (m, 4H), 1.721.59 (m, 4H), 1.110.99 (m, 12H); 13C{1H} NMR (101 MHz, CDCl3)  157.2, 154.0, 152.6, 144.7, 141.9, 138.8, 134.1, 128.9, 127.9, 127.7, 122.1, 116.6, 114.5, 113.3, 112.3, 37.2, 32.8, 29.6, 28.4, 23.6, 23.1, 21.5, 21.3, 14.5, 14.3, 14.2, 13.9. 5-Nitro-2,3,7,8-tetrapropylpyrano[4,3,2-ij]isoquinoline (3j):


Page 20 of 45

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3j (62 mg, 54%); yellow crystalline solid. mp  173174 C; 1H NMR (400 MHz, CDCl3)  8.26 (s, 1H), 7.62 (s, 1H), 2.892.76 (m, 4H), 2.602.47 (m, 4H), 1.801.70 (m, 4H), 1.661.55 (m, 4H), 1.100.97 (m, 12H); 13C{1H} NMR (101 MHz, CDCl3)  156.7, 155.8, 154.8, 150.5, 138.3, 136.3, 124.1, 117.2, 113.8, 113.6, 112.3, 106.5, 37.1, 32.8, 29.6, 28.4, 23.4, 23.3, 21.3, 14.1, 13.9, 13.8; IR (Neat) max 2957, 2929, 1643, 1571, 1524, 1453, 1337, 1243, 1129, 1053, 875 cm1; HRMS (ESI) for C23H31N2O3 (M+H)+: calcd. 383.2329, found 383.2334. 2,3,7,8-Tetrapropyl-5-(trifluoromethyl)pyrano[4,3,2-ij]isoquinoline (3k): 3k (78 mg, 64%); yellow crystalline solid. mp  158159 C; 1H NMR (400 MHz, CDCl3)  7.65 (s, 1H), 7.06 (s, 1H), 2.862.77 (m, 4H), 2.592.45 (m, 4H), 1.821.72 (m, 4H), 1.651.55 (m, 4H), 1.100.97 (m, 12H);

13

C{1H} NMR (101 MHz, CDCl3)  156.8, 155.0, 153.8, 138.0,

135.1, 133.4 (d, J  31.3 Hz), 125.5, 122.8 (d, J  18.1 Hz), 116.4, 115.1, 112.1, 109.0, 37.2, 32.8, 29.5, 28.3, 23.1, 21.3, 21.2, 14.3, 14.2, 14.1, 13.8; 19F NMR (376 MHz, CDCl3) 63.24; IR (Neat) max 2957, 2931, 1644, 1584, 1417, 1288, 1174, 1110, 962 cm1 ; HRMS (ESI) for C24H31F3NO (M+H)+: calcd. 406.2352, found 406.2358. Methyl 2,3,7,8-tetraethylpyrano[4,3,2-ij]isoquinoline-5-carboxylate (3l): 3l (50 mg, 49%); yellow crystalline solid. mp  173174 C; 1H NMR (400 MHz, CDCl3)  8.14 (s, 1H), 7.52 (s, 1H), 3.97 (s, 3H), 2.952.80 (m, 4H), 2.622.52 (m, 4H), 1.331.25 (m, 6H), 1.241.13 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3)  167.2, 157.1, 155.1, 154.0, 137.7, 133.9, 132.8, 124.2, 120.1, 117.2, 113.2, 112.8, 52.4, 28.1, 24.1, 20.5, 19.4, 14.5, 14.4, 13.0. 12.6; IR (Neat) max 2963, 2931, 1718, 1644, 1583, 1435, 1402, 1346, 1272, 1244, 1210, 1167, 1140, 1056 cm1; HRMS (ESI) for C21H26NO3 (M+H)+: calcd. 340.1907, found 340.1908.



4-Methyl-2,3,7,8-tetrapropylpyrano[4,3,2-ij]isoquinoline (3m): 14 3m (50 mg, 47%); pale yellow crystalline solid. mp  9899 C; 1H NMR (400 MHz, CDCl3) 7.347.24 (m, 2H), 2.792.69 (m, 4H), 2.6546 (m, 7H), 1.821.68 (m, 4H), 1.621.44 (m, 4H), 1.070.95 (m, 12H); 13C{1H} NMR (101 MHz, CDCl3)  156.7, 153.9, 150.8, 137.7, 137.5, 131.1, 123.9, 121.6, 118.5, 117.1, 113.5, 36.9, 33.2, 30.1, 29.6, 24.0, 23.5, 23.0, 22.8, 21.6, 14.4, 14.3, 14.0, 13.7. 2,3,7,8-Tetraethyl-5-methylpyrano[4,3,2-ij]isoquinoline (3n): 14 3n (58 mg, 65%); light yellow crystalline solid. mp  136137 C; 1H NMR (400 MHz, CDCl3)

 7.12 (s, 1H), 6.80 (s, 1H), 2.862.76 (m, 4H), 2.582.45 (m, 7H), 1.331.24 (m, 6H), 1.231.11 (m, 6H);

13

C{1H} NMR (101 MHz, CDCl3)  157.2, 154.5, 153.0, 142.0, 138.5,

133.1, 122.3, 117.3, 115.0, 114.0, 112.9, 28.1, 24.0, 22.9, 20.4, 19.4, 14.6, 14.1, 13.0, 12.6. 2,3,7,8-Tetrabutyl-5-methylpyrano[4,3,2-ij]isoquinoline (3o): 14 3o (83 mg, 68%); light yellow crystalline solid. mp  8082C; 1H NMR (400 MHz, CDCl3)  7.16 (s, 1H), 6.75 (s, 1H), 2.80(m, 4H), 2.542.39 (m, 7H), 1.741.64 (m, 4H), 1.561.36 (m, 12H), 1.010.90 (m, 12H);

13

C{1H} NMR (101MHz, CDCl3)  157.1, 153.6, 152.1, 141.8,

138.6, 133.3, 121.2, 117.4, 115.1, 113.7, 111.9, 34.9, 32.5, 31.8, 30.6, 30.3, 30.0, 27.1, 26.0, 23.0, 22.98, 22.93, 22.8, 22.5, 14.0, 13.91, 13.88, 13.80. 2,3,7,8-Tetrakis(methoxymethyl)-5-methylpyrano[4,3,2-ij]isoquinoline (3p): 3p (78 mg, 73%); light yellow crystalline solid. mp  117118 C; 1H NMR (400 MHz, CDCl3)

 7.51 (s, 1H), 7.16 (s, 1H), 4.76(s, 2H), 4.63(s, 2H), 4.48(s, 2H), 4.37(s, 2H), 3.43(s, 3H), 3.411(s, 3H), 3.407(s, 3H), 3.39(s, 3H), 2.51(s, 3H);

13

C{1H} NMR (101MHz, CDCl3) 


Page 22 of 45

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157.9, 152.2, 149.2, 143.3, 139.1, 131.3, 120.4, 120.0, 118.7, 115.2, 113.4, 73.8, 69.0, 66.8, 66.3, 58.5, 58.3, 57.9, 57.7, 22.9; IR (Neat) max 2919, 2809, 1738, 1658, 1609, 1584, 1486, 1418, 1338, 1220, 1187, 1079, 946 cm1; HRMS (ESI) for C20H26NO5 (M+H)+: calcd. 360.1805, found 360.1812. 3,4-Diethyl-8-methylisoquinolin-1(2H)-one (3r): 3r (56 mg, 87%); colorless solid. 1H NMR (400 MHz, CDCl3)  11.66 (bs, 1H), 7.587.46 (m, 2H), 7.18 (d, J  6.8 Hz, 1H), 2.99 (s, 3H), 2.792.67 (m, 4H), 1.35 (t, J = 7.4 Hz, 3H), 1.20 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3 )  165.1, 142.0, 139.9, 139.4, 131.4, 128.3, 123.6, 120.9, 113.5, 24.0, 23.9, 19.8, 14.8, 13.9; IR (Neat) max 2958, 2922, 1644, 1630, 1594, 1554, 1465, 1357, 1225, 1183, 906 cm1 ; HRMS (ESI) for C14H17NNaO (M+Na)+: calcd. 238.1202, found 238.1201. A Stepwise Unsymmtrical Double-annulation of N-Methoxybenzamide Derivatives 1 with Different Alkynes for the Synthesis of 6,6-Fused Pyrano-Isoquinoline (GP-2): Step I: First Annulation of 1 with Alkynes (2a/2b) for the Synthesis of Isoquinolone (GP2A): The annulation reactions were carried out in a 25 mL screw capped tube. The tube was charged with N-methoxybenzamide derivatives (1, 0.5 mmol), alkynes (2a/2b, 0.6 mmol), [RuCl2(pcymene)]2 (9.2 mg, 3.0 mol%, 0.015 mmol), and sodium acetate (8.2 mg, 20 mol%, 0.1 mmol). MeOH (3.0 mL) was added to the mixture and the resulting mixture was stirred at room temprature for 10 h. The reaction mixture was filtered through a small plug of Celite and then washed with dichloromethane (3×10 mL). The solvents were evaporated under reduced pressure and the crude material was purified using column chromatography on silica gel (20-25% nhexane/EtOAc eluent) to give the desired product.



Page 24 of 45

6-Methyl-3,4-dipropylisoquinolin-1(2H)-one (4a): 14 4a (108 mg, 89%, 0.5 mmol); colorless crystalline solid. mp 195197 C; 1H NMR (400 MHz, CDCl3) 10.96 (bs, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.25 (s, 1H), 2.722.62 (m, 4H), 2.51 (s, 3H), 1.74 (q, J = 7.6 Hz, 2H), 1.60 (q, J = 7.6 Hz, 2H), 1.081.01 (m, 6H);

13

C{1H}

NMR (101 MHz, CDCl3) 163.6, 142.6, 138.6, 138.1, 127.6, 126.8, 122.9, 122.8, 112.6, 32.9, 28.5, 23.5, 22.7, 22.3, 14.3, 13.9. 3,4-Diethyl-6-phenylisoquinolin-1(2H)-one (4b): 4b (119 mg, 86%, 0.5 mmol); colorless crystalline solid. mp 285286 C; 1H NMR (400 MHz, CDCl3) 11.24 (bs, 1H), 8.54 (d, J 8.0 Hz, 1H), 7.87 (d, J 0.8 Hz, 1H), 7.737.64 (m, 3H), 7.51 (t, J 7.4 Hz, 2H), 7.43 (t, J 7.4 Hz, 1H), 2.882.72 (m, 4H), 1.37 (t, J 7.6 Hz, 3H), 1.27 (t, J 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) 163.8, 145.2, 140.9, 139.6, 138.6, 128.9, 128.3, 128.0, 127.6, 124.7, 124.0, 121.2, 114.0, 24.3, 19.5, 15.0, 14.0; IR (Neat) max 2963, 2868, 1646, 1544, 1490, 1416, 1337, 1259, 1165, 1020 cm ; HRMS (ESI) for C19H20NO (M+H)+: calcd. 278.1539, found. 278.1547. 6-Bromo-3,4-diethylisoquinolin-1(2H)-one (4c): 4c (122 mg, 87%, 0.5 mmol); colorless crystalline solid. mp 251252 C; 1H NMR (400 MHz, CDCl3) 11.35 (bs, 1H), 8.30 (d, J 8.4 Hz, 1H), 7.82 (d, J 1.6 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 2.772.66 (m, 4H), 1.33 (t, J 7.6 Hz, 3H), 1.20 (t, J 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) 163.5, 140.8, 139.8, 129.5, 128.6, 127.9, 125.6, 123.7, 113.1, 24.3, 19.4, 14.8, 13.9; IR (Neat) max 2966, 2872, 1654, 1592, 1450, 1333, 1304, 1076, 901, 870, cm; HRMS (ESI) for C13H15BrNO (M+H)+: calcd. 280.0332, found. 280.0331.


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Step II: Procedure for Second Annulation of Isoquinolone (4) with Alkynes (2) (GP-2B): The annulation reactions were carried out in a 25 mL screw capped tube. The tube was charged with isoquinolone (4, 0.3 mmol), alkyne (2, 0.36 mmol), [RuCl2(p-cymene)]2 (9.2 mg, 5.0 mol %, 0.015 mmol), and Cu(OAc)2·H2O (60 mg, 0.3 mmol). Subsequently, AgSbF6 (20.6 mg, 20 mol %, 0.06 mmol) was introduced in to the flask in a glove box. The solvent 1,2-dichloroethane (DCE) (2.0 mL) was added to the mixture and the resulting mixture was stirred at 120 C in heating block for 20 h. The reaction mixture was cooled to ambient temperature, filtered through a small plug of Celite and then washed with dichloromethane (3 × 10 mL). Solvents were evaporated under reduced pressure and the crude material was purified using column chromatography on neutral aluminia (510% n-hexane/EtOAc eluent) to give the desired product. Following this procedure (GP-2B), compounds 5al were prepared. Analytical and spectral data of these compounds are exactly matching with the reported values. 14 5-Methyl-2,3-diphenyl-7,8-dipropylpyrano[4,3,2-ij]isoquinoline (5a): 5a (95 mg, 75%); yellow crystalline solid. mp  180181 C; 1H NMR (400 MHz, CDCl3)  7.457.35 (m, 5H), 7.307.24 (m, 3H), 7.237.13 (m, 3H), 6.53 (s, 1H), 2.892.81 (m, 4H), 2.39 (s, 3H), 1.881.78 (m, 2H), 1.721.62 (m, 2H), 1.161.04 (m, 6H);

13

C{1H} NMR (101 MHz,

CDCl3)  157.0, 152.4, 150.6, 142.0, 138.5, 135.0, 134.3, 133.5, 130.8, 129.3, 129.0, 128.4, 127.6, 127.4, 121.8, 118.6, 118.1, 117.2, 113.6, 37.0, 29.5, 23.5, 22.9, 22.7, 14.4, 14.2; IR (Neat)

max 2953, 2868, 1673, 1577, 1470, 1373, 1339, 1218, 1157, 1097, 873, 709 cm1; HRMS (ESI) for C30H30NO (M+H)+: calcd. 420.2322, found 420.2322. 2,3-Bis(4-(tert-butyl)phenyl)-5-methyl-7,8-dipropylpyrano[4,3,2-ij]isoquinoline (5b):



Page 26 of 45

5b (143 mg, 89%); yellow crystalline solid. mp  192193 C; 1H NMR (400 MHz, CDCl3)  7.42 (d, J 8.0 Hz, 2H), 7.29 (d, J 8.8 Hz, 2H), 7.23 (s, 1H), 7.17 (t, J 8.4 Hz, 4H), 6.53 (s, 1H), 2.862.78 (m, 4H), 2.37 (s, 3H), 1.871.74 (m, 2H), 1.711.58 (m, 2H), 1.38 (s, 9H), 1.26 (s, 9H), 1.131.01 (m, 6H);

13

C{1H} NMR (101 MHz, CDCl3)  157.2, 152.4, 151.4, 150.5,

150.4, 142.0, 138.5, 134.8, 132.2, 130.7, 130.4, 128.9, 125.9, 124.3, 121.7, 118.3, 118.1, 116.7, 113.7, 37.0, 34.6, 34.5, 31.3, 31.1, 29.6, 23.5, 22.9, 22.8, 14.4, 14.2; IR (Neat) max 2956, 2867, 1631, 1577, 1505, 1466, 1362, 1267, 1241, 1220, 1110, 1017, 841 cm1; HRMS (ESI) for C38H46NO (M+H)+: calcd. 532.3574, found 532.3580. 2,3-Bis(4-methoxyphenyl)-5-methyl-7,8-dipropylpyrano[4,3,2-ij]isoquinoline (5c): 14 5c (111 mg, 77%); yellow crystalline solid. mp  159160 C; 1H NMR (400 MHz, CDCl3)  7.31 (d, J 8.4 Hz, 2H), 7.21 (s, 1H), 7.14 (d, J 8.4 Hz, 2H), 6.93 (d, J 8.4 Hz, 2H), 6.68 (d, J 8.4 Hz, 2H), 6.49 (s, 1H), 3.82 (s, 3H), 3.73 (s, 3H), 2.80 (t, J 8.0 Hz, 4H), 2.35 (s, 3H), 1.79 (q, J 7.46 Hz, 2H), 1.63 (q, J 7.6 Hz, 2H), 1.111.00 (m, 6H);

13

C{1H} NMR (101

MHz, CDCl3)  159.4, 158.8, 157.1, 152.3, 150.4, 142.0, 138.5, 134.9, 131.9, 130.7, 127.4, 126.0, 121.7, 118.2, 117.8, 115.7, 114.5, 113.5, 112.8, 55.1, 55.0, 37.0, 29.5, 23.5, 22.9, 22.7, 14.4, 14.2. 2,3-Bis(4-fluorophenyl)-5-methyl-7,8-dipropylpyrano[4,3,2-ij]isoquinoline (5d): 14 5d (123 mg, 90%); light yellow crystalline solid. mp  194195 C; 1H NMR (400 MHz, CDCl3)

 7.357.28 (m, 2H), 7.25 (bs, 1H), 7.227.14 (m, 2H), 7.08 (t, J .6 Hz, 2H), 6.85 (t, J 8.8 Hz, 2H), 6.44 (s, 1H), 2.852.76 (m, 4H), 2.37 (s, 3H), 1.78 (q, J 7.7 Hz, 2H), 1.63 (q, J 7.7 Hz, 2H), 1.120.99 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3)  163.6 (d, J  30 Hz), 161.1 (d, J  28 Hz), 156.8, 152.5, 149.9, 142.1, 138.6, 134.0, 132.6 (d, J  8.0 Hz), 131.2 (d, J  9.0 Hz),


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130.8 (d, J  3.0 Hz), 129.5 (d, J  3.0 Hz), 122.1, 118.9, 118.0, 116.4, 116.2 (d, J  4.0 Hz), 114.7 (d, J  21 Hz), 113.5, 37.0, 29.5, 23.4, 22.9, 22.7, 14.4, 14.2;

19

F NMR (376 MHz,

CDCl3)111.44, 113.44. 2,3-Bis(4-chlorophenyl)-5-methyl-7,8-dipropylpyrano[4,3,2-ij]isoquinoline (5e): 5e (70 mg, 48%); yellow crystalline solid. mp  195196 C; 1H NMR (400 MHz, CDCl3)  7.38 (d, J 8.4 Hz, 2H), 7.28 (s, 1H), 7.26 (s, 2H), 7.15 (dd, J 8.2 Hz, 2.2 Hz, 4H), 6.43 (s, 1H), 2.852.76 (m, 4H), 2.37 (s, 3H), 1.77 (q, J 7.6 Hz, 2H), 1.62 (q, J 7.6 Hz, 2H), 1.120.99 (m, 6H);

13

C{1H} NMR (101 MHz, CDCl3)  156.7, 152.6, 149.7, 142.1, 138.6,

134.7, 133.8, 133.6, 133.3, 132.2, 131.7, 130.6, 129.6, 128.0, 122.2, 119.1, 118.1, 116.5, 113.5, 37.0, 29.6, 23.5, 22.9, 22.8, 14.4, 14.2; IR (Neat) max 2955, 2868, 1628, 1575, 1479, 1402, 1337, 1261, 1157, 1086, 833 cm1; HRMS (ESI) for C30H28Cl2NO (M+H)+: calcd. 488.1542, found 488.1539. 1,1'-((5-Methyl-7,8-dipropylpyrano[4,3,2-ij]isoquinoline-2,3-diyl)bis(4,1phenylene))diethanone (5f): 14 5f (114 mg, 75%); yellow crystalline solid. mp  215216 C; 1H NMR (400 MHz, CDCl3)  7.97 (d, J 6.8 Hz, 2H), 7.71 (d, J 7.2 Hz, 2H), 7.40 (d, J 6.8 Hz, 2H), 7.32 (d, J 6.8 Hz, 2H), 7.26 (d, J 4.0 Hz, 1H), 6.41 (s, 1H), 2.832.74 (m, 4H), 2.61 (s, 3H), 2.51 (s, 3H), 2.34 (s, 3H), 1.821.69 (m, 2H), 1.671.54 (m, 2H), 1.090.96 (m, 6H);

13

C{1H} NMR (101 MHz,

CDCl3)  197.4, 197.3, 156.5, 152.6, 149.6, 142.1, 139.9, 138.6, 137.5, 136.6, 136.5, 133.1, 131.1, 129.4, 129.2, 127.6, 122.4, 119.4, 118.3, 117.7, 113.5, 37.0, 29.5, 26.54, 26.50, 23.4, 22.9, 22.7, 14.4, 14.2.



Page 28 of 45

5-Methyl-7,8-dipropyl-2,3-di-m-tolylpyrano[4,3,2-ij]isoquinoline (5g): 5g (100 mg, 75%); light yellow crystalline solid. mp  131132 C; 1H NMR (400 MHz, CDCl3)

 7.34 (bs, 1H), 7.327.23 (m, 2H), 7.17 (d, J 7.6 Hz, 1H), 7.086.97 (m, 5H), 6.50 (s, 1H), 2.872.79 (m, 4H), 2.38 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H), 1.871.74 (m, 2H), 1.681.58 (m, 2H), 1.131.06 (m, 6H), 13C{1H} NMR (101 MHz, CDCl3)  157.2, 152.4, 150.6, 142.1, 138.6, 137.0, 135.1, 134.6, 133.4, 131.3, 129.8, 129.2, 128.8, 128.3, 127.9, 127.1, 126.5, 121.8, 118.5, 118.1, 117.2, 113.7, 37.1, 29.6, 23.5, 22.9, 22.8, 21.4, 21.2, 14.4, 14.2; IR (Neat) max 2955, 2924, 1630, 1573, 1470, 1400, 1339, 1268, 1148, 1083, 1039 cm1 ; HRMS (ESI) for C32H34NO (M+H)+: calcd. 448.2635, found 448.2639. 2,3-Diethyl-5-methyl-7,8-dipropylpyrano[4,3,2-ij]isoquinoline (5h): 14 5h (57 mg, 59%); light yellow crystalline solid. mp  9394 C; 1H NMR (400 MHz, CDCl3)  7.17 (s, 1H), 6.78 (s, 1H), 2.802.70 (m, 4H), 2.572.46 (m, 7H), 1.791.69 (m, 2H), 1.631.54 (m, 2H), 1.27 (t, J 7.4 Hz, 3H), 1.15 (t, J 7.6 Hz, 3H), 1.090.96 (m, 6H);

13

C{1H} NMR

(101 MHz, CDCl3)  157.1, 154.4, 152.0, 141.9, 138.8, 133.1, 121.3, 117.5, 115.0, 113.8, 112.9, 37.1, 29.5, 24.0, 23.5, 22.92, 22.91, 19.4, 14.4, 14.2, 13.0, 12.7. 3-Butyl-5-methyl-2-phenyl-7,8-dipropylpyrano[4,3,2-ij]isoquinoline (5i): 5i (91 mg, 76%); yellow crystalline solid. mp  151152 C; 1H NMR (400 MHz, CDCl3)  7.607.54 (m, 2H), 7.467.39 (m, 3H), 7.27 (s, 1H), 6.41 (s, 1H), 2.852.72 (m, 4H), 2.552.46 (m, 5H), 1.801.70 (m, 2H), 1.691.55 (m, 4H), 1.34 (q, J 7.3 Hz, 2H), 1.08 (t, J 7.4 Hz, 3H), 1.00 (t, J 7.2 Hz, 3H), 0.87 (t, J 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3)  157.0, 152.2, 151.1, 141.8, 138.7, 134.2, 133.1, 129.1, 128.8, 128.0, 121.6, 118.3, 116.2, 114.02, 113.97, 37.0, 30.4, 29.5, 26.7, 23.4, 23.0, 22.9, 22.6, 14.4, 14.2, 13.7; IR (Neat) max 2953, 2927,


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1641, 1606, 1581, 1461, 1338, 1286, 1242, 1133, 946 cm1 ; HRMS (ESI) for C28H34NO (M+H)+: calcd. 400.2635, found 400.2638. 1-(4-(5-Methyl-2-phenyl-7,8-dipropylpyrano[4,3,2-ij]isoquinolin-3-yl)phenyl)ethanone (5j) and 1-(4-(5-Methyl-3-phenyl-7,8-dipropylpyrano[4,3,2-ij]isoquinolin-2-yl)phenyl)ethanone (5j′): 5j and 5j′ (3:2, 122 mg, 88%); yellow crystalline solid. mp  174176 C; 1H NMR (400 MHz, CDCl3)  7.96 (d, J 8.4 Hz, 1.5H), 7.71 (d, J 8.8 Hz, 2H), 7.43 (d, J 8.4 Hz, 2H), 7.417.29 (m, 6H), 7.25 (s, 1H), 7.247.17 (m, 2H), 7.167.10 (m, 2H), 6.49 (s, 1H), 6.41 (s, 0.75H), 2.842.77 (m, 7H), 2.60 (s, 2H), 2.51 (s, 3H), 2.372.32 (m, 5H), 1.78 (q, J 7.7 Hz, 3.5H), 1.62 (q, J 7.7 Hz, 3.6H), 1.110.98 (m, 10.8H);

13

C{1H} NMR (101 MHz, CDCl3) 

197.5, 197.4, 156.8, 156.7, 152.6, 152.5, 151.0, 149.2, 142.1, 142.0, 140.5, 138.6, 138.5, 138.0, 136.3, 136.2, 134.6, 133.8, 133.6, 133.1, 131.3, 130.7, 129.35, 129.29, 129.2, 129.0, 128.8, 128.0, 127.6, 127.4, 122.1, 119.2, 118.9, 118.7, 118.6, 117.8, 116.3, 113.7, 113.5, 37.0, 29.5, 26.50, 26.47, 23.44, 23.41, 22.9, 22.7, 14.4, 14.2; IR (Neat) max 2955, 2926, 2868, 1674, 1631, 1603, 1576, 1441, 1263, 1219, 1185, 1098, 956 cm1 ; HRMS (ESI) for C32H32NO2 (M+H)+: calcd. 462.2428, found 462.2425. 3-Butyl-7,8-diethyl-2,5-diphenylpyrano[4,3,2-ij]isoquinoline (5k): 5k (101 mg, 78%); yellow crystalline solid. mp  186187 C; 1H NMR (400 MHz, CDCl3)  7.747.67 (m, 3H), 7.62 (dd, J 7.8 & 1.4 Hz, 2H), 7.587.41 (m, 6H), 7.32 (s, 1H), 3.022.84 (m, 4H), 2.60 (t, J 8.0 Hz, 2H), 1.741.62 (m, 2H), 1.531.26 (m, 8H), 0.90 (t, J 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3)  157.1, 153.6, 151.5, 144.7, 141.7, 138.5, 134.0, 133.9, 129.2, 129.0, 128.9, 128.1, 127.9, 127.6, 123.3, 117.1, 114.8, 114.3, 30.4, 28.1, 26.7, 22.6, 20.6,



14.5, 14.2, 13.7; IR (Neat) max 2951, 2867, 1637, 1579, 1469, 1371, 1286, 1128, 1026, 941 cm1; HRMS (ESI) for C31H32NO (M+H)+: calcd. 434.2478, found 434.2478. 5-Bromo-3-butyl-7,8-diethyl-2-phenylpyrano[4,3,2-ij]isoquinoline (5l): 5l (94 mg, 72%); yellow crystalline solid. mp  188189 C; 1H NMR (400 MHz, CDCl3)  7.63 (d, J 1.2 Hz, 1H), 7.607.53 (m, 2H), 7.477.40 (m, 3H), 7.14 (d, J 1.2 Hz, 1H), 2.882.78 (m, 4H), 2.48 (t, J 8.0 Hz, 2H), 1.631.54 (m, 2H), 1.401.18 (m, 8H), 0.87 (t, J 7.4 Hz, 3H);

13

C{1H} NMR (101 MHz, CDCl3)  156.9, 154.6, 152.3, 139.4, 135.4, 133.6,

129.3, 129.1, 128.1, 127.5, 122.6, 120.8, 117.7, 114.2, 113.5, 30.2, 28.2, 26.7, 22.6, 20.5, 14.4, 14.1, 13.7; IR (Neat) max 2959, 2928, 1637, 1578, 1559, 1447, 1339, 1313, 1219, 1129, 1097 cm1; HRMS (ESI) for C25H26BrNNaO (M+Na)+: calcd. 458.1090, found 458.1091. General Procedure for the One-Pot Double Annulations of N-Methoxybenzamide with Two Different Alkynes (2) (GP-3): The annulation reactions were carried out in a 25 mL screw capped tube. The tube was charged with 1 (50 mg, 0.3 mmol), 2a (0.3 mmol), [RuCl2 (p-cymene)]2 (18.4 mg, 10 mol%, 0.03 mmol), and Cu(OAc)2·H2O (90 mg, 0.45 mmol). Subsequently, AgSbF6 (41 mg, 40 mol %, 0.12 mmol) was introduced in to the tube in a glove box. The solvent 1,2-dichloroethane (DCE) (2.0 mL) was added to the mixture and the resulting mixture was stirred at 60 C in heating block for 4 h. Upon completion of mono-annulation, another alkyne 2g/2f (0.36 mmol) was added to the above reaction mixture. The resulting mixture was then heated at 120 C in heating block for 20 h. The reaction mixture was cooled to ambient temperature, filtered through a small plug of Celite and then washed with dichloromethane (3 × 10 mL). The solvents were evaporated under reduced


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pressure and the crude material was purified using column chromatography on silica gel (5-10% n-hexane/EtOAc eluent) to give desired product. 7,8-Diethyl-5-methyl-2,3-diphenylpyrano[4,3,2-ij]isoquinoline (6a): 6a (58 mg, 57%); light yellow crystalline solid. mp  212213 C; 1H NMR (400 MHz, CDCl3)

 7.42 (d, J 8.4 Hz, 2H), 7.28 (d, J  Hz, 2H), 7.26 (s, 1H), 7.207.12 (m, 4H), 6.52 (s, 1H), 2.932.81 (m, 4H), 2.38 (s, 3H), 1.37 (s, 9H), 1.33 (t, J 7.6 Hz, 3H), 1.271.20 (m, 12H); 13

C{1H} NMR (101 MHz, CDCl3)  157.3, 153.3, 151.4, 150.6, 150.4, 142.2, 138.3, 134.9,

132.2, 130.7, 130.5, 128.9, 125.9, 124.3, 122.7, 118.2, 118.1, 116.7, 113.8, 34.6, 34.5, 31.4, 31.1, 28.2, 22.8, 20.5, 14.7, 14.2; IR (Neat) max 2959, 2867, 1631, 1578, 1505, 1460, 1361, 1267, 1199, 1110, 1016, 838 cm1; HRMS (ESI) for C36H42NO (M+H)+: calcd. 504.3261, found 504.3268. 7,8-Diethyl-5-methyl-2,3-diphenylpyrano[4,3,2-ij]isoquinoline (6b): 6b (56 mg, 71%); light yellow crystalline solid. mp  187189 C; 1H NMR (400 MHz, CDCl3)

 7.417.34 (m, 5H), 7.307.22 (m, 3H), 7.217.12 (m, 3H), 6.51 (s, 1H), 2.942.83 (m, 4H), 2.37 (s, 3H), 1.34 (t, J 7.4 Hz, 3H), 1.25 (t, J 7.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3)

 157.1, 153.3, 150.6, 142.2, 138.3, 135.1, 134.4, 133.5, 130.9, 129.3, 129.0, 128.5, 127.6, 127.5, 122.8, 118.4, 118.1, 117.2, 113.7, 28.1, 22.8, 20.5, 14.7, 14.1; IR (Neat) max 2957, 2869, 1639, 1579, 1447, 1375, 1341, 1228, 1125, 1055 cm1; HRMS (ESI) for C28H26NO (M+H)+: calcd. 392.2009, found 392.2007. Gram Scale Synthesis of 3a:



The annulation reactions were carried out in a 50 mL screw capped tube. The tube was charged with N-methoxy-4-methylbenzamide (1a, 6.05 mmol), 4-octyne (2a, 18.15 mmol), [RuCl2(pcymene)]2 (0.370 g, 10 mol %, 0.605 mmol), and Cu(OAc)2·H2O (1.81 g, 9.07 mmol). Subsequently, AgSbF6 (0.831 g, 40 mol %, 2.42 mmol) was introduced in to the tube in a glove box. The solvent 1,2-dichloroethane (DCE) (15.0 mL) was added to the mixture and the resulting mixture was stirred at 120 C in heating block for 24 h. The reaction mixture was cooled to ambient temperature, filtered through a small plug of Celite and then washed with dichloromethane (3 × 20 mL). The solvents were evaporated under reduced pressure and the crude material was purified using column chromatography on neutral aluminia (510% nhexane/EtOAc eluent). The compound 3a (1.55 g) was isolated in 73% yield. Synthisis of 1,4-bis(2,3,7,8-tetrapropylpyrano[4,3,2-ij]isoquinolin-5-yl)benzene (7):15 A mixture of compound benzene-1,4-diboronic acid (16.5 mg, 0.1 mmol), 3h (83 mg, 0.2 mmol), Pd(PPh3)4 (11.5 mg, 10 mol%, 0.01 mmol) and K2CO3 (35 mg, 0.25 mmol) in THF (1.5 mL), EtOH (1.0 mL) and H2O (0.5 mL) was taken in a screw capped tube and heated at 85 oC heating block for 20 h. The reaction mixture was extracted with ethylacetate (3  15 mL), dried over Na2SO4 and concentrated under vacuum. The crude material was purified by silica gel column chromatograpy eluting with hexane to give 7 (57 mg) in 76% yield as yellow crystalline solid; mp  280282 C; 1H NMR (400 MHz, CDCl3)  7.82 (s, 4H), 7.63 (s, 2H), 7.21 (s, 2H), 2.88 (t, J  7.4 Hz, 4H), 2.81 (t, J  7.6 Hz, 4H), 2.602.51 (m, 8H), 1.851.73 (m, 8H), 1.721.61 (m, 8H), 1.13-0.99 (m, 24H); 13C{1H} NMR (101 MHz, CDCl3)  157.2, 154.1, 152.7, 144.0, 141.5, 138.8, 134.2, 128.2, 122.1, 116.5, 114.6, 113.1, 112.2, 37.2, 32.8, 29.6, 28.4, 23.6, 23.1, 21.5, 21.3, 14.5, 14.31, 14.27, 13.9; IR (Neat) max 2954, 2926, 1641, 1581, 1466, 1337, 1203, 1165, 1089, 1047 cm1; HRMS (ESI) for C52H65N2O2 (M+H)+: calcd. 749.5041, found 749.5039.


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Synthesis of 5-(phenylethynyl)-2,3,7,8-tetrapropylpyrano[4,3,2-ij]isoquinoline (8):17 Phenylacetylene (24.5 mg, 0.24 mmol) and triethylamine (83 µL, 0.6 mmol) was added to a stirred suspension of compound 3h (90.5 mg, 0.20 mmol), PdCl2(PPh3)2 (5.6 mg, 4 mol %, 0.008 mmol), CuI (2.3 mg, 6 mol %, 0.012 mmol) in DMF (1.5 mL) under nitrogen atmosphere. The reaction mixture was heated at 100 oC in heating block for 10 h. After completion, the reaction mixture was cooled to ambient temperature, filtered through a small plug of Celite and then washed with EtOAc. The solvents were evaporated under reduced pressure. The crude mixture was extracted with ethylacetate (3 × 5 mL). The organic layer was dried over Na2SO4. Solvent was filtered and evaporated under the reduced pressure. The crude residue was purified using column chromatography on silica gel to afford 8 (74 mg) in 84% yield as yellow crystalline solid; mp  143144 C; 1H NMR (400 MHz, CDCl3)  7.657.57 (m, 2H), 7.58 (s, 1H), 7.407.34 (m, 3H), 7.03 (s, 1H), 2.842.73 (m, 4H), 2.572.43 (m, 4H), 1.821.71 (m, 4H), 1.671.56 (m, 4H), 1.120.97 (m, 12H); 13C{1H} NMR (101MHz, CDCl3)  156.9, 154.1, 153.9, 138.1, 133.8, 131.7, 128.6, 128.4, 126.5, 122.8, 121.8, 121.5, 115.9, 114.6, 111.8, 90.5, 90.1, 37.2, 32.8, 29.6, 28.3, 23.5, 23.1, 21.4, 21.2, 14.5, 14.3, 14.2, 13.9; IR (Neat) max 2955, 2928, 1640, 1578, 1491, 1405, 1335, 1207, 1129, 914 cm1 ; HRMS (ESI) for C31H36NO (M+H)+: calcd. 438.2791, found 438.2795. Synthisis

of

5,5'-(2-(pyridin-2-yl)-1,3-phenylene)bis(2,3,7,8-tetrapropylpyrano[4,3,2-

ij]isoquinoline) (9):17 A mixture of 2-phenylpyridine (15.5 mg, 0.1 mmol), 3h (103.8 mg, 0.25 mmol), [RuCl2(pcymene)]2 (1.5 mg, 2.5 mol%, 0.0025 mmol), and KOAc (29 mg, 0.3 mmol) in Nmethylpyrrolidine (NMP; 1.0 mL) was taken in a screw capped tube and heated at 120 oC in



Page 34 of 45

heating block for 5 h. The reaction mixture was extracted with ethylacetate (3  10 mL), dried over Na2SO4, and concentrated under vacuum. The crude material was purified by silica gel column chromatograpy eluting with 10% n-hexane/EtOAc to give compound 9 (68 mg) in 82% yield as yellow crystalline solid; mp  182183 C; 1H NMR (400 MHz, CDCl3)  8.32 (d, J  4.4 Hz, 1H), 7.64 (t, J  7.6 Hz, 1H), 7.607.50 (m, 2H), 7.31 (t, J  7.6 Hz, 1H), 7.23 (s, 2H), 7.00 (q, J  7.6 Hz, 1H), 6.916.84 (m, 1H), 6.72 (s, 2H), 2.72 (t, J  8.0 Hz, 4H), 2.63 (t, J  7.8 Hz, 4H), 2.46 (t, J  7.6 Hz, 4H), 2.25 (t, J  7.6 Hz, 4H), 1.751.69 (m, 8H), 1.451.22 (m, 8H), 1.030.88 (m, 24H); 13C{1H} NMR (101 MHz, CDCl3)  158.4, 157.1, 153.6, 152.2, 149.1, 145.0, 142.4, 138.2, 138.1, 135.2, 132.9, 130.3, 128.6, 126.3, 121.9, 121.1, 119.3, 115.7, 114.0, 112.1, 37.1, 32.7, 29.5, 28.2, 23.5, 22.9, 21.3, 21.2, 14.5, 14.3, 14.2, 13.8; IR (Neat) max 2928, 2869, 1645, 1580, 1457, 1365, 1338, 1203, 1126, 1054, 859 cm1; HRMS (ESI) for C57H68N3O2 (M+H)+: calcd. 826.5306, found 826.5307. ASSOCIATED CONTENT AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; [email protected] Supporting Information The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org Deuterium studies, Competition experiments, and 1H and compounds (PDF) ORCID


13

C{1H} NMR spectra for all

Page 35 of 45 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


Akhila K. Sahoo: 0000-0001-5570-4759 Tirumaleswararao Guntreddi: 0000-0003-0566-0895 Majji Shankar: 0000-0003-3758-9069 Nagarjuna Kommu: 0000-0001-7366-3305 Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We thank SERB (EMR/2014/385) for financial support and University of Hyderabad (UoH; UPE-CAS and PURSE-FIST) for overall facility. T.G. thanks SERB-NPDF, M.S. thanks CSIR, N.K. thanks ACRHEM, for fellowship. Author Contributions †

T.G. and M.S. contributed equally.

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8. (a) Sarkar, D.; Melkonyan, F. S.; Gulevich, A.V.; Gevorgyan, V.; Twofold Unsymmetrical CH Functionalization of PyrDipSiSubstituted Arenes: A General Method for the Synthesis of Substituted metaHalophenols. Angew.Chem.Int. Ed.


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10. (a) Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Rhodium-catalyzed Oxidative Coupling/Cyclization of Benzamides with Alkynes via C–H Bond Cleavage. Chem.Lett. 2010, 39, 744746. (b) Song, G.; Chen, D.; Pan, C.L.; Crabtree, R. H.; Li, X. Rh-Catalyzed Oxidative Coupling between Primary and Secondary Benzamides and Alkynes: Synthesis of Polycyclic Amides. J. Org. Chem. 2010, 75, 74877490. (c) G.-T. Zhang.; Dong, L. Synthesis of Polycyclic Amides via Tandem RhIII-Catalyzed CH Activation and Annulation from Dioxazolones and Alkynes. Asian J. Org. Chem. 2017, 6, 812816. 11. (a) Tan, X.; Liu, B.; Li, X.; Li, B.; Xu, S.; Song, H.; Wang, B. Rhodium-Catalyzed Cascade Oxidative Annulation Leading to Substituted Naphtho[1,8-bc]pyrans by Sequential Cleavage of C(sp2)–H/C(sp3)–H and C(sp2)–H/O–H Bonds. J. Am. Chem. Soc. 2012, 134, 1616316166. (b) Parthasarathy, J. K.; Chen, Y.-H.; Lee, T.-H.; Chuang, S.-C.; Cheng, C.-H. One‐Pot Synthesis of Highly Substituted Polyheteroaromatic

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12. (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Palladium(II)‐Catalyzed CH Activation/CC Cross‐Coupling Reactions: Versatility and Practicality. Angew. Chem., Int. Ed. 2009, 48, 50945115. (b) 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6801. 13. (a) Ghorai, D.; Choudhury, J. Rhodium(III)–N-Heterocyclic Carbene-Driven Cascade C– H Activation Catalysis. ACS Catal. 2015, 5, 26922696. (b) Ge, Q.; Li, B.; Song, H.; Wang, B. Rhodium(III)-catalyzed cascade oxidative annulation reactions of aryl imidazolium salts with alkynes involving multiple C–H bond activation. Org. Biomol. Chem. 2015, 13, 76957710. (c) Ge, Q.; Hu, Y.; Li, B.; Wang, B. Synthesis of Conjugated Polycyclic Quinoliniums by Rhodium(III)-Catalyzed Multiple C–H Activation and Annulation of Arylpyridiniums with Alkynes. Org. Lett. 2016, 18, 24832486. 14. Shankar, M.; Ghosh, K.;

Mukherjee, K.; Rit, R.

K.; Sahoo, A.

K.

One-Pot

Unsymmetrical {[4 + 2] and [4 + 2]} Double Annulations of o/o′-C–H Bonds of Arenes: Access to Unusual Pyranoisoquinolines. Org. Lett. 2018, 20, 51445148. 15. The reaction of 1 with 1,2-diaryl acetylene (2) generally provides the respective polycyclic amide (linear annulation product; see ref 9). For example, the reaction of 1a with 1,2-diphenyl acetylene (2f) delivered the polycyclic amide with trace amount of the desired pyrano-isoquinolines.



16. The reaction of 1a with two different alkynes [3-hexyne (2b) and 1,2-diphenyl acetylene (2f)] provided a mixture of annulation products; consequently, the purification is tedious and unsuccessful. 17. (a) Burke, M. J.; Nichol, G. S.; Lusby, P. J. Orthogonal Selection and Fixing of Coordination Self-Assembly Pathways for Robust Metallo-Organic Ensemble Construction. J. Am. Chem. Soc. 2016, 138, 93089315. (b) Malamas, M.S.; Barnes, K.; Johnson, M. et al. Di-substituted pyridinyl aminohydantoins as potent and highly selective human β-secretase (BACE1) inhibitors. Bioorg Med. Chem., 2010, 18, 630639. (c) Pozgan, F.; Dixneuf, P. H. Ruthenium(II) Acetate Catalyst for Direct Functionalisation of sp 2‐CH Bonds with Aryl Chlorides and Access to Tris‐ Heterocyclic Molecules. Adv. Synth. Catal. 2009, 351, 17371743. 18. Simmons, E. M.; Hartwig, J. F. On the Interpretation of Deuterium Kinetic Isotope Effects in CH Bond Functionalizations by Transition‐Metal Complexes. Angew. Chem., Int. Ed. 2012, 51, 30663072. 19. See the Supporting Information. 20. (a) Mio, M. J.; Kopel, L. C.; Braun, J. B.; Gadzikwa, T. L.; Hull, K. L.; Brisbois, R. G.; Markworth, C. J.; Grieco, P. A. One-Pot Synthesis of Symmetrical and Unsymmetrical Bisarylethynes by a Modification of the Sonogashira Coupling Reaction. Org. Lett. 2002, 4, 31993202. (b) Park, K.; Bae, G.; Moon, J.; Choe, J.; Song, K. H.; Lee, S. Synthesis of Symmetrical and Unsymmetrical Diarylalkynes from Propiolic Acid Using Palladium-Catalyzed Decarboxylative Coupling. J.


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Org. Chem. 2010, 75, 62446251. (c) Zhou, B.; Lu, A.; Shao, C.; Liang, X.; Zhang, Y. Palladium-Catalyzed Sequential Three-Component Reactions to Access Vinylsilanes. Chem. Commun. 2018, 54, 1059810601.


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